Cephalosporin derivatives

ABSTRACT

What are disclosed are anti-bacterially active cephalosporin compounds of the formula ##STR1## pharmaceutical preparations containing such compounds, methods of making the compounds, methods for combatting bacterial infections therewith, and intermediates for such compounds.

The present invention relates to new cephalosporin derivatives and to a process for their preparation, in particular to polar cephem derivatives which are substituted in the 3-position of the cephem ring by certain pyridiniummethyl radicals and which have a very good antimicrobial action against Gram-positive and Gram-negative bacteria and which are therefore highly suitable for use as medicaments for treating microbial infections.

The invention therefore relates to cephem derivatives of the general formula I ##STR2## wherein R¹ denotes hydrogen or halogen, R² denotes hydrogen or C₁ -C₆ -alkyl, A denotes a pyridinium radical ##STR3## which can be monosubstituted or multisubstituted by identical or different substituents, namely by optionally substituted C₁ -C₆ -alkyl, of which 2 alkyl groups can be linked to form a possibly substituted di- to deca-methylene ring in which one C atom can be replaced by a heteroatom and which can additionally contain one or two double bonds, by cyano-C₁ -C₃ -alkyl, epoxy-C₂ -C₆ -alkyl, trifluoromethyl or pentafluoroethyl, by hydroxyiminomethyl or C₁ -C₄ -alkoxyiminomethyl, by optionally substituted C₂ -C₆ -alkenyl, by C₂ -C₆ -alkynyl, by C₃ -C₇ -cycloalkyl or C₃ -C₇ -cycloalkylmethyl, in which two substituents the ring can also be substituted, by C₄ -C₇ -cycloalkenyl, by optionally substituted C₁ -C₆ -alkoxy, by epoxy-C₂ -C₆ -alkoxy, by C₂ -C₆ -alkenyloxy or C₂ -C₆ -alkynyloxy, by halogen, cyano, hydroxyl or mercapto, by C₁ -C₆ -alkylsulfonyl, C₁ -C₆ -alkylsulfinyl or C₁ -C₆ -alkythio which is optionally substituted in the alkyl part, by methylsulfonyl, methylsulfinyl or methylthio which is substituted on the methyl radical, by C₂ -C₆ -alkenylthio, C₂ -C₆ -alkenylsulfinyl or C₂ -C₆ -alkenylsulfonyl, by optionally substituted phenyl, benzyl or heteroaryl, by formyl or ketalized formyl, by optionally substituted C₁ -C₆ -alkylcarbonyl which can also be present in ketalized form, by arylcarbonyl, by C₁ -C₆ -alkylcarbonylamino, by carboxyl or C₁ -C₆ -alkoxycarbonyl, by carbamoyl, which can be monosubstituted or disubstituted on the nitrogen, by optionally substituted carbazoyl, by sulfamoyl, which can be monosubstituted on the nitrogen, or by pyridyl or 4-pyridon-1-yl, and wherein the R² O group is in the syn position.

The present invention relates in particular to compounds in which R¹ and R² have the abovementioned meanings and A denotes a pyridinium radical ##STR4## which can be 1-substituted or multisubstituted by identical or different substituents, namely by C₁ -C₆ -alkyl which can be monosubstituted or multisubstituted by hydroxyl, carboxyl, C₁ -C₆ -alkyloxycarbonyl, formyl or C₁ -C₆ -alkylcarbonyl, the carbonyl groups of which can also be present in ketalized form, carbamoyl, N-hydroxycarbamoyl, sulfo, C₁ -C₆ -alkyloxy, hydroxy-C₁ -C₆ -alkyloxy, C₁ -C₆ -alkylthio, C₁ -C₆ -alkylsulfinyl, C₁ -C₆ -alkylsulfonyl, C₂ -C₆ -alkenyloxy, C₂ -C₆ -alkenylthio, C₂ -C₆ -alkenylsulfinyl or C₂ -C₆ -alkenylsulfonyl, and of which 2 alkyl groups can also be linked to form an optionally substituted di- to deca-methylene ring in which one C atom can be replaced by one heteroatom and which can additionally contain one or two double bonds, by cyano-C₁ -C₃ -alkyl, epoxy-C₂ -C₆ -alkyl, trifluoromethyl, hydroxyiminomethyl or C₁ -C₄ -alkoxyiminomethyl, pentafluoroethyl, by C₂ -C₆ -alkenyl which can be substituted by hydroxyl, by C₂ -C₆ -alkynyl, by C₃ -C₇ -cycloalkyl or C₃ -C₇ -cycloalkylmethyl, in which two substituents the ring can also be substituted by hydroxyl, halogen, carboxyl, C₁ -C₆ -alkyloxycarbonyl or cyano, by C₄ -C₇ -cycloalkenyl, by C₁ -C₆ -alkoxy, which can be substituted by hydroxyl, carboxyl or C.sub. 1 -C₆ -alkyloxycarbonyl, by epoxy-C₂ -C₆ -alkoxy, by C₂ -C₆ -alkenyloxy or C₂ -C₆ -alkynyloxy, by halogen, cyano, hydroxyl or mercapto, by C₁ -C₆ -alkylthio, C₁ -C₆ -alkylsulfinyl or C₁ -C₆ -alkylsulfonyl, all of which can be substituted by hydroxyl in the alkyl part, by methylthio, methylsulfinyl or methylsulfonyl, all of which are substituted in the methyl part by carboxyl or C₁ -C₆ -alkyloxycarbonyl, by C₂ -C₆ -alkenylthio, C₂ -C₆ -alkenylsulfinyl or C₂ -C₆ -alkenylsulfonyl, by phenyl, benzyl or heteroaryl, all of which can also be substituted by halogen, by formyl or ketalized formyl, by C₁ -C₆ -alkylcarbonyl which can also be substituted by hydroxyl and can also be present in ketalized form, by arylcarbonyl or C₁ -C₆ -alkylcarbonylamino, by carboxyl or C₁ -C₆ -alkoxycarbonyl, by carbamoyl which can be monosubstituted on the nitrogen by C₁ -C₆ -alkyl, hydroxy-C₁ -C₆ -alkyl, C₁ -C₆ -alkyloxycarbonyl, C₁ -C₆ -alkylcarbonyl, carboxymethyl, C₁ -C₆ -alkyloxycarbonylmethyl, aminocarbonylmethyl, C₁ -C₆ -alkylaminocarbonyl, carbamoyl, hydroxyl or pyridyl, or which can be disubstituted on the nitrogen by C₁ -C₆ -alkyl, by carbazoyl which can be substituted by C₁ -C₄ -alkyl, or N-carbamoylcarbazoyl, by sulfamoyl which can be monosubstituted on the nitrogen by C₁ -C₆ -alkylaminocarbonyl, or by pyridyl or 4-pyridon-1-yl, and in which preferred compounds of the general formula I the R² O group is also in the syn position.

Possible substituents for the di- to deca-methylene ring mentioned under A, in which one C atom can be replaced by one heteroatom and one or two double bonds can additionally be contained, are in particular the following substituents, which can occur once or several times but preferably occur once: C₁ -C₆ -alkyl, C₁ -C₄ -alkoxy, hydroxymethyl, halogen, hydroxyl, oxo, hydroxyimino, exomethylene, carboxyl, C₁ -C₆ -alkyloxycarbonyl, cyano or carbamoyl.

These substituents can occur in the rings which have been mentioned and are fused onto the pyridinium radical, regardless of whether the particular ring is saturated, unsaturated or, additionally, interrupted by a heteroatom. However, according to the invention the substituents preferably occur on fused-on saturated rings which do not contain any heteroatoms.

The ring fused onto the pyridinium radical can contain 2 to 20 ring members (di- to deca-methylene), but it preferably contains 3 to 5 ring members and it can thus be, for example, a cyclopenteno, cyclohexeno or cyclohepteno ring. If such a fused-on ring contains a double bond, then the examples which may be mentioned are a dehydrocyclopenteno, dehydrocyclohexeno or dehydrocyclohepteno ring. If in such rings one C atom is replaced by one heteroatom, the latter can be in particular oxygen or sulfur. Examples which may be mentioned of fused-on rings which each contain one oxygen atom and two or one double bonds are furo, pyrano, dihydrofuro and dihydropyrano, and examples of fused-on rings which each have one sulfur atom and contain two or one double bonds are thieno, thiopyrano, dihydrothieno and dihydrothiopyrano. Among the fused-on rings which each contain one heteroatom, candidates for a substitution, in particular by the abovementioned substituents, are in particular those rings which contain only one double bond.

Examples of particularly preferable substituents are: R¹ : hydrogen, chlorine and fluorine, in particular chlorine, R² : hydrogen, C₁ -C₄ -alkyl, such as, for example, methyl, ethyl, propyl, isopropyl, preferably methyl, ethyl, in particular methyl, A: a pyridinium radical which can be monosubstituted or multisubstituted, preferably 1- to 3-fold, in particular 1- to 2-fold, for example by C₁ -C₄ -alkyl, such as, in particular, methyl, ethyl, propyl, isopropyl, n-butyl, sec.-butyl, tert.-butyl, dimethyl, trimethyl, methyl and ethyl, methyl and propyl, methyl and isopropyl, ethyl and ethyl, hydroxy-C₁ -C₄ -alkyl, such as in particular, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, hydroxybutyl, hydroxy-sec.-butyl or hydroxy-tert.-butyl, and in which it is also possible for the alkyl radical to be substituted by two or three hydroxyl groups, carboxy-C₁ -C₄ -alkyl, such as, in particular, carboxymethyl and carboxyethyl, C₁ -C₄ -alkyloxycarbonyl-C₁ -C₄ -alkyl, such as, in particular, methyloxycarbonylmethyl, ethyloxycarbonylmethyl, methyloxycarbonylethyl, formyl-C₁ -C₄ -alkyl, such as, in particular, formylmethyl, C₁ -C₄ -alkylcarbonyl-C₁ -C₄ -alkyl, such as, in particular, methylcarbonylmethyl, ethylcarbonylmethyl, methylcarbonylethyl and ethylcarbonylethyl, the two alkyl groups of which can also be further substituted by hydroxyl and the carbonyl group of which can also be present in the ketalized form, carbamoyl-C₁ -C₄ -alkyl, such as, in particular, carbamoylmethyl and carbamoylethyl, which can also be further substituted by hydroxyl on the nitrogen, such as, in particular, N-hydroxycarbamoylmethyl, sulfo-C₁ -C₄ -alkyl, such as, in particular, sulfoethyl or 1-hydroxy-1-sulfomethyl, C₁ -C₄ -alkyloxy-C₁ -C₄ -alkyl, such as, in particular, methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, methoxyethyl, ethoxyethyl, methoxypropyl and methoxyisopropyl, all of which can be substituted by hydroxyl, such as, in particular, hydroxyethoxymethyl and hydroxyethoxyethyl, C₁ -C.sub. 4 -alkylthio-C₁ -C₄ -alkyl, such as, in particular, methylthiomethyl, ethylthiomethyl, methylthioethyl and ethylthioethyl, C₁ -C₄ -alkylsulfinyl-C₁ -C₄ -alkyl, such as, in particular, methylsulfinylmethyl, ethylsulfinylmethyl, methylsulfinylethyl and ethylsulfinylethyl, C₁ -C₄ -alkylsulfonyl-C₁ -C₄ -alkyl, such as, in particular, methylsulfonylmethyl, ethylsulfonylmethyl, methylsulfonylethyl and ethylsulfonylethyl, C₃ -alkenyloxy-C₁ -C₄ -alkyl, such as, in particular, allyloxymethyl and allyloxyethyl, C₃ -alkenylthio-C₁ -C₄ -alkyl, such as, in particular, allylthiomethyl, C₃ -alkenylsulfinyl-C₁ -C₄ -alkyl, such as, in particular, allylsulfinylmethyl, C₃ -alkenylsulfonyl-C₁ -C₄ -alkyl, such as, in particular, allylsulfonylmethyl, cyano-C₁ -C₃ -alkyl, such as, in particular, cyanomethyl and cyanoethyl, epoxy-C₂ -C₃ -alkyl, such as, in particular, epoxyethyl and epoxypropyl, trifluoromethyl, hydroxyiminomethyl and C₁ -C₃ -alkoxyiminomethyl, such as, in particular, methoxyiminomethyl, C₃ -C₄ -alkenyl, such as, in particular, allyl, 2-methylallyl and buten-3-yl, all of which can also be further substituted by hydroxyl, such as, in particular, hydroxyallyl and hydroxybutenyl, C₃ -alkynyl, such as, in particular, propargyl, C₃ -C₆ -cycloalkyl and C₃ -C₆ -cycloalkylmethyl, in which the number of carbons relates to the cycloalkyl part, such as, in particular, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclopentylmethyl, in which the rings can also be substituted, for example, by hydroxyl, such as, in particular, 1-hydroxy-1-cyclopentyl and 1-hydroxy- 1-cyclohexyl, or by halogen, preferably chlorine, by carboxyl, C₁ -C₄ -alkoxycarbonyl or cyano, C₅ -C₆ -cycloalkenyl, such as, in particular, cyclopenten-1-yl and cyclohexen-1-yl, C₁ -C₄ -alkoxy, such as, in particular, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and tert.-butoxy, preferably methoxy, all of which alkoxy groups can also be further substituted, for example, by hydroxyl, carboxyl or C₁ -C₄ -alkoxycarbonyl, in particular carboxymethoxy and methoxycarbonylmethoxy, epoxy-C₂ -C₃ -alkoxy, such as, in particular, epoxyethoxy or epoxypropoxy, C₃ -alkenyloxy, such as, in particular, allyloxy, C₃ -alkynyloxy, such as, in particular, propargyloxy, halogen, such as, in particular, fluorine, chlorine, bromine or iodine, cyano, hydroxyl, in particular 3-hydroxy, C₁ -C₄ -alkylthio, such as, in particular, methylthio, ethylthio, propylthio and isopropylthio, all of which can also be substituted by hydroxyl, in particular hydroxyethylthio, C₁ -C₄ -alkylsulfinyl, such as, in particular, methylsulfinyl, ethylsulfinyl, propylsulfinyl and isopropylsulfinyl, all of which can also be substituted by hydroxyl, in particular hydroxyethylsulfinyl, C₁ -C₄ -alkylsulfonyl, such as methylsulfonyl, ethylsulfonyl, propylsulfonyl or isopropylsulfonyl, all of which can also be substituted by hydroxyl, in particular hydroxyethylsulfonyl, carboxymethylthio and C₁ -C₄ -alkoxycarbonylmethylthio, in particular methoxycarbonylmethylthio, carboxymethylsulfinyl and carboxymethylsulfonyl, C₁ -C₄ -alkoxycarbonylmethylsulfinyl and -alkoxycarbonylmethylsulfonyl, in particular methoxycarbonylmethylsulfinyl and methoxycarbonylmethylsulfonyl, C₃ -alkenylthio, such as allylthio and propen-1-ylthio, C₃ -alkenylsulfinyl, such as allylsulfinyl and propen-1-ylsulfinyl, C₃ alkenylsulfonyl, such as allylsulfonyl and propen-1-ylsulfonyl, phenyl and benzyl, both of which can also be substituted, for example by halogen, in particular chlorine, such as, for example, 4-chlorobenzyl, 2'-thienyl and 3'-thienyl, formyl and ketalized formyl, such as, for example, 1,3-dioxolan-2-yl, C₁ -C₄ -alkylcarbonyl, in particular acetyl and propionyl, preferably acetyl, which can also be substituted by hydroxyl and be present in ketalized form, such as, for example, 2-methyl-1,3-dioxolan-2-yl, benzoyl, C₁ -C₄ -alkylcarbonylamino, in particular acetylamino and propionylamino, formylamino, carboxyl, for example also 2,3,4-carboxy, C₁ -C₄ -alkoxycarbonyl, in particular methoxycarbonyl and ethoxycarbonyl, such as, for example, also 2,3,4-methoxycarbonyl or 2,3,4-ethoxycarbonyl, carbamoyl (for example also 2,3,4-carbamoyl) which can be monosubstituted on the nitrogen atom by C₁ -C₄ -alkyl, such as, in particular, N-methylcarbamoyl and N-ethylcarbamoyl, by hydroxy-C₁ -C₄ -alkyl, such as, in particular, N-hydroxymethylcarbamoyl and N-hydroxyethylcarbamoyl, by C₁ -C₄ -alkoxycarbonyl, such as, in particular, N-methoxycarbonylcarbamoyl and N-ethoxycarbonylcarbamoyl, by C₁ -C₄ -alkylcarbonyl, such as, in particular, N-acetylcarbamoyl, by carboxymethyl, by C₁ -C₄ -alkoxycarbonylmethyl, such as, in particular, N-methoxycarbonylmethylcarbamoyl and N-ethoxycarbonylmethylcarbamoyl, by aminocarbonylmethyl, by N-C₁ -C₄ -alkylaminocarbonyl, such as, in particular, N-methylaminocarbonylcarbamoyl and N-ethylaminocarbonylcarbamoyl, by carbamoyl (=ureidocarbonyl), by hydroxyl or pyridyl, such as, in particular, N-3'-pyridylcarbamoyl and N-4'-pyridylcarbamoyl, N-C₁ -C₄ -dialkylcarbamoyl, such as, in particular, N,N-dimethylcarbamoyl and N,N-diethylcarbamoyl, carbazoyl which can be substituted by C₁ -C₄ -alkyl, in particular methyl or ethyl, by carbamoyl, such as N-carbamoylcarbazoyl, sulfamoyl, which can be substituted on the nitrogen atom by C₁ -C₄ -alkylaminocarbonyl, such as, in particular, ethylaminocarbonylsulfamoyl, and pyridyl, such as, in particular, 2'-, 3'- and 4'-pyridyl and 4-pyridon-1-yl.

If A represents a pyridinium radical which is substituted by two alkyl groups which are linked to form a di- to deca-methylene ring which in turn can be monosubstituted or multisubstituted but preferably is monosubstituted and can contain one or two double bonds, examples of this are in particular the following fused-on ring systems: cyclopenteno, hydroxycyclopenteno, chlorocyclopenteno, bromocyclopenteno, oxocyclopenteno, hydroxymethylcyclopenteno, exomethylenecyclopenteno, carboxycyclopenteno, C₁ -C₄ -alkoxycarbonylcyclopenteno, in particular methoxycarbonylcyclopenteno and carbamoylcyclopenteno, cyclohexeno, hydroxycyclohexeno, chlorocyclohexeno, bromocyclohexeno, oxocyclohexeno, hydroxymethylcyclohexeno, exomethylenecyclohexeno, carboxycyclohexeno, C₁ -C₄ -alkoxycarbonylcyclohexeno, in particular methoxycarbonylcyclohexeno and carbamoylcyclohexeno, cyclohepteno, hydroxy-, chloro-, bromo-, oxo-, hydroxymethyl-, exomethylene- or carboxy-cyclohepteno, in particular methoxycarbonylcyclohepteno and carbamoylcyclohepteno, dehydrocyclopenteno, dehydrocyclohexeno and dehydrocyclohepteno.

If in the abovementioned fused-on ring systems one C atom is replaced by one heteroatom, in particular oxygen or sulfur, possible examples are in particular: 2,3- and 3,4-furo, 2,3- and 3,4-pyrano, 2,3- and 3,4-dihydrofuro, 2,3- and 3,4-dihydropyrano, methyldihydrofuro, methoxydihydropyrano and hydroxydihydropyrano.

The invention also relates to a process for preparing compounds of the formula I and their physiologically acceptable acid addition salts, which process comprises reacting a) a compound of the general formula II ##STR5## or its salts, wherein R¹ and R² have the abovementioned meaning and R³ denotes a group which can be replaced by pyridine or substituted pyridines which correspond to the pyridinium radicals A of the formula I, with pyridine or such a pyridine derivative or b) reacting a 7-aminocephem compound of the general formula III ##STR6## or its acid addition salts, in which the amino group can also be present in the form of a reactive derivative, with a 2-(2-aminothiazol-4-yl)-2-syn-oximinoacetic acid of the general formula IV ##STR7## wherein R¹ and R² have the above meaning and R⁴ represents hydrogen or an amino protective group or with an activated derivative of this compound and α) eliminating a protective group, if present, and β) if necessary, converting the product obtained into a physiologically acceptable acid addition salt.

If the compounds of the general formula I are to be prepared by a nucleophilic replacement reaction of R³ in the compounds of the general formula II by pyridine or one of the pyridine derivatives indicated, possible examples of radicals R³ are in particular acyloxy radical of lower aliphatic carboxylic acids, preferably having 1 to 4 C atoms, such as, for example, acetoxy or propionyloxy, in particular acetoxy, which radicals may be substituted, such as, for example, chloroacetoxy or acetylacetoxy. Other groups are also possible for R³ such as, for example, halogen, in particular chlorine or bromine, or carbamoyloxy.

Starting compounds of the general formula II in which R³ represents acetoxy, or their salts, such as, for example, a sodium salt or potassium salt, are used, according to the invention, in the nucleophilic replacement reaction. The reaction is carried out in a solvent, preferably in water, or in a mixture of water and an organic solvent which is readily miscible with water, such as, for example, acetone, dioxane, acetonitrile, dimethylformamide, dimethylsulfoxide or ethanol. The reaction temperature is in general within the range from about 10° to about 100° C., preferably between 20° and 80° C. The pyridine component is added in amounts which are between approximately equimolar amounts and not more than an approximately 5-fold excess. The replacement of the radical R³ is facilitated by the presence of neutral salt ions, preferably of iodide or thiocyanate ions, in the reaction medium. In particular, about 10 to about 30 equivalents of potassium iodide, sodium iodide, potassium thiocyanate or sodium thiocyanate are added. The reaction is advantageously carried out under approximately neutral conditions, preferably at a pH value within the range from about 5 to about 8.

If R³ represents a carbamoyloxy group, the replacement reaction is carried out analogously. If R³ represents halogen, in particular bromine, the replacement is effected in a manner described in the literature.

The acylation of the compounds of the general formula III or of their addition salts, for example with hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid or an organic acid, such as, for example, methanesulfonic acid or p-toluenesulfonic acid, can be carried out by means of carboxylic acids of the general formula IV or by means of a reactive derivative of such an acid. In this step, it is in some cases advantageous to protect the 2-amino group in the compounds of the general formula IV from the reaction. Suitable examples of amino protective groups R⁴ are optionally substituted alkyl, such as, for example, tert.-butyl, tert.-amyl, benzyl, p-methoxybenzyl, trityl, benzhydryl, preferably trityl, trialkylsilyl, such as, for example, trimethylsilyl, optionally substituted aliphatic acyl, such as, for example, formyl, chloroacetyl, bromoacetyl, trichloroacetyl and trifluoroacetyl, preferably chloroacetyl, or optionally substituted alkoxycarbonyl, such as, for example, trichloroethoxycarbonyl, benzyloxycarbonyl or tert.-butoxycarbonyl, preferably tert.-butoxycarbonyl and benzyloxycarbonyl.

After the acylation, the protective group can be split off in a manner which is in itself known, for example the trityl group by means of a carboxylic acid, such as, for example acetic acid or formic acid, or the chloroacetyl group by means of thiourea.

If the carboxylic acids of the general formula IV and their derivatives protected at the amino group are themselves used as acylating agents, the reaction is advantageously carried out in the presence of a condensing agent, for example of a carbodiimide, such as, for example, N,N'-dicyclohexylcarbodiimide.

The activation of the carboxylic acids of the general formula IV can be particularly advantageously effected by treatment with certain carboxamides and, for example, phosgene, phosphorus pentachloride, tosyl chloride, thionyl chloride or oxalyl chloride, as described in German Patent 2,804,040.

Suitable activated derivatives of the carboxylic acids of the general formula IV are in particular also halides, preferably chlorides, which can be obtained in a manner which is in itself known by treatment with halogenating agents, such as, for example, phosphorus pentachloride, phosgene or thionyl chloride, under mild reaction conditions described in cephalosporin chemistry literature.

Further suitable activated derivatives of the carboxylic acids of the general formula IV are the anhydrides and mixed anhydrides, azides and activated esters, preferably those formed with p-nitrophenol, 2,4-dinitrophenol, methylenecyanohydrin, N-hydroxysuccinimide and N-hydroxyphthalimide, in particular those formed with 1-hydroxybenzotriazole and 6-chloro-1-hydroxybenzotriazole. Particularly suitable mixed anhydrides are those formed with lower alkanoic acids, such as, for example, acetic acid, and particularly preferably those formed with substituted acetic acids, such as, for example, trichloroacetic acid, pivalic acid or cyanoacetic acid. However, those mixed anhydrides are also particularly suitable which are formed with carbonic acid half-esters, which are obtained, for example, by reacting the carboxylic acids of the formula IV, in which the amino group is protected, with benzyl chloroformate, p-nitrobenzyl chloroformate, isobutyl chloroformate, ethyl chloroformate or allyl chloroformate. The activated derivatives can be reacted as isolated substances or in situ.

Generally, the reaction of the cephem derivatives of the general formula III with a carboxylic acid of the general formula IV or with an activated derivative thereof is carried out in the presence of an inert solvent. Particularly suitable solvents are chlorinated hydrocarbons, such as, for example, methylene chloride and chloroform, ethers, such as, for example, diethyl ether, preferably tetrahydrofuran and dioxan, ketones, such as preferably acetone and butanone, amides, such as preferably dimethylformamide and dimethylacetamide, or water. It can also be advantageous to use mixtures of the solvents mentioned. This can be advantageous in many cases where the cephem compound of the general formula III is reacted with an activated derivative of a carboxylic acid of the formula IV which derivative has been formed in situ.

The reaction of cephem compounds of the formula III with carboxylic acids of the formula IV or with activated derivatives thereof can be carried out within a temperature range of about -80° to about +80° C., preferably between -30° and +50° C., but in particular between about -20° C. and room temperature.

The reaction time depends on the reactants, the temperature and the solvent or the mixture of solvents and normally is between about 1/4 and about 72 hours.

The reaction with acid-halides may be carried out in the presence of an acid-binding agent to bind the hydrogen halide liberated. Suitable acid-binding agents are in particular tertiary amines, such as, for example, triethylamine or dimethylaniline, inorganic bases, such as, for example, potassium carbonate or sodium carbonate, or alkylene oxides, such as, for example, propylene oxide. The presence of a catalyst, such as, for example, of dimethylaminopyridine, may also be advantageous.

If in the compounds of the general formula III the amino group is present in the form of a reactive derivative, the latter can be of a type described in the literature for amidation. Possible examples are thus silyl derivatives which are formed when compounds of the general formula III are reacted with a silyl compound, such as, for example, trimethylsilylchlorosilane or bis-(trimethylsilyl)-acetamide. If the reaction is carried out with one of these compounds which are activated at the amino group, it is advantageous to carry out the reaction in an inert solvent, such as, for example, methylene chloride, tetrahydrofuran or dimethylformamide.

Physiologically acceptable acid addition salts of compounds of the general formula I which may be mentioned by way of example are those salts formed with hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid or with organic acids, such as, for example, methanesulfonic acid or p-toluenesulfonic acid.

Compounds of the general formula III can be obtained in a manner which is in itself known (cf, for example, German Offenlegungsschrift 3,019,838), for example from 7-aminocephalosporanic acid protected at the amino group, in the same way as described above for the nucleophilic replacement of R³.

Compounds of the general formula IV and the pyridine derivatives which correspond to the pyridinium radicals A are known from the literature or can be prepared by methods described in the literature.

Compounds of the general formula I, obtained according to the invention, and their physiologically acceptable acid addition salts have remarkably high antibacterial actions, not only against Gram-positive but also against Gram-negative bacterial germs.

The compounds of the formula I are also unexpectedly highly active against penicillinase- and cephalosporinase-forming bacteria. Since these compounds additionally have favorable toxicological and pharmacological properties, they are valuable chemotherapeutic agents.

The invention thus also relates to medicaments for treating microbial infections and which contain one or more of the compounds according to the invention.

The products according to the invention can also be used in combination with other active compounds, for example of the series of the penicillins, cephalosporins or aminoglycosides.

The compounds of the general formula I and their physiologically acceptable acid addition salts can be administered orally, intramuscularly or intravenously. Medicaments which contain one or more compounds of the general formula I as active compound can be prepared by mixing the compounds of the formula I with one or more pharmacologically acceptable excipients or diluents, such as, for example, fillers, emulsifiers, lubricants, taste corrigents, colorants or buffer substances and bringing the mixtures into a suitable galenic administration form, such as, for example, tablets, coated tablets, capsules or a solution or suspension suitable for parenteral administration.

Examples which may be mentioned of excipients or diluents are tragacanth, lactose, talc, agar-agar, polyglycols, ethanol and water. Preferably suspensions or solutions in water are used for parenteral administration. It is also possible to administer the active compounds as such, without excipients or diluents, in a suitable form, for example in capsules.

Suitable doses of compounds of the general formula I or of their physiologically acceptable acid addition salts are from about 0.4 to 20 g per day, preferably 0.5 to 4 g per day, for an adult weighing about 60 kg.

Single, or in general, multiple doses can be administered, and the single dose can contain the active compound in an amount from about 50 to 1,000 mg, preferably from about 100 to 500 mg.

Cephem compounds which carry a substituted pyridiniummethyl radical in the 3-position of the cephem ring are known from German Offenlegungsschriften 2,921,316, 2,716,707 and 2,715,385.

In addition to the products described in the illustrative examples it is also possible to prepare, according to the invention, compounds which correspond, for example, to the general formula I' ##STR8## in which --OCH₃ is in the syn position and A' represents

a) a pyridinium radical which is substituted by radicals indicated in Table 1 or

b) a radical shown in Table 2.

In Table 1, the numbers show the position of the substituent(s) on the pyridinium radical.

                                      TABLE 1                                      __________________________________________________________________________     2,3-di-CH.sub.3 2,5-di-CH.sub.3 2-Propyl 3-Propyl                                           3-Cyclobutyl 4-Cyclobutyl 2-Cyclopentyl 3-Cyclopentyl                                        ##STR9##                                            2-Isopropyl 2-n-Butyl 3-n-Butyl                                                             4-Cyclopentyl 2-Cyclopentylmethyl 3-Cyclopentylmethyl                                        ##STR10##                                           4-n-Butyl 2-sec-Butyl 3-sec-Butyl                                                           4-Cyclopentylmethyl 2-Cyclohexyl 3-Cyclohexyl                                                ##STR11##                                           4-sec-Butyl  4-Cyclohexyl 2-CH.sub.2 OH-3-CH.sub.3                             2-tert-Butyl 2-Cyclopentyl-3-CH.sub.3                                                                    2-CH.sub.2 OH-4-CH.sub.3                             3-tert-Butyl 2-Cyclopentyl-4-CH.sub.3                                                                    2-CH.sub.2 OH-5-CH.sub.3                             2-C.sub.2 H.sub.5 -3-CH.sub.3                                                               2-Cyclopentyl-5-CH.sub.3                                                                    3-CH.sub.2 OH-2-CH.sub.3                             2-C.sub.2 H.sub.5 -4-CH.sub.3                                                               3-Cyclopentyl-4-CH.sub.3                                                                    3-CH.sub.2 OH-4-CH.sub.3                             2-C.sub.2 H.sub.5 -5-CH.sub.3                                                               3-Cyclopentyl-5-CH.sub.3                                                                    3-CH.sub.2 OH-5-CH.sub.3                             3-C.sub.2 H.sub.5 -2-CH.sub.3                                                               4-Cyclopentyl-2-CH.sub.3                                                                    3-CH.sub.2 OH-6-CH.sub.3                             3-C.sub.2 H.sub.5 -5-CH.sub.3                                                               4-Cyclopentyl-3-CH.sub.3                                                                    4-CH.sub.2 OH-2-CH.sub.3                             4-C.sub.2 H.sub.5 -2-CH.sub.3                                                               2-(1-Cyclopenten-1-yl)                                                                      4-CH.sub.2 OH-3-CH.sub.3                             4-C.sub.2 H.sub.5 -3-CH.sub.3                                                               3-(1-Cyclopenten-1-yl)                                                                      2-CH.sub.2 OH-3-C.sub.2 H.sub.5                      2,3,4-triCH.sub.3                                                                           4-(1-Cyclopenten-1-yl)                                                                      2-CH.sub.2 OH-4-C.sub.2 H.sub.5                      2,3,5-triCH.sub.3                                                                           2-(1-Cyclohexen-1-yl)                                                                       2-CH.sub.2 OH-5-C.sub. 2 H.sub.5                     2,4,5-triCH.sub.3                                                                           3-(1-Cyclohexen-1-yl)                                                                       3-CH.sub.2 OH-2-C.sub.2 H.sub.5                      3,4,5-triCH.sub.3                                                                           4-(1-Cyclohexen-1-yl)                                                                       3-CH.sub.2 OH-4-C.sub.2 H.sub.5                      2-CH.sub.2 CHCH.sub.2                                                                       2-CH.sub.2 CCH                                                                              3-CH.sub.2 OH-5-C.sub.2 H.sub.5                      3-CH.sub.2 CHCH.sub.2                                                                       3-CH.sub.2 CCH                                                                              3-CH.sub.2 OH-6-C.sub.2 H.sub.5                      4-CH.sub.2 CHCH.sub.2                                                                       4-CH.sub.2 CCH                                                                              4-CB.sub.2 OH-2-C.sub.2 H.sub.5                      2-CH.sub.2 CH.sub.2 CHCH.sub.2 3-CH.sub.2 CH.sub.2 CHCH.sub.2 4-CH.sub.2       CH.sub.2 CHCH.sub.2                                                                          ##STR12##   4-CH.sub.2 OH-3-C.sub.2 H.sub.5 2-CH.sub.2                                     OH-3,4-diCH.sub.3 2-CH.sub.2 OH-3,5-diCH.sub.3       2-CH.sub.2 C(CH.sub.3)CH.sub.2 3-CH.sub.2 C(CH.sub.3)CH.sub.2 4-CH.sub.2       C(CH.sub.3)CH.sub.2 2-Cyclopropyl                                                            ##STR13##   2-CH.sub.2 OH-4,5-diCH.sub.3 3-CH.sub.2                                        OH-2,4-diCH.sub.3 3-CH.sub.2 OH-2,5-diCH.sub.3                                 3-CH.sub.2 OH-4,5-diCH.sub.3                         3-Cyclopropyl 4-Cyclopropyl 2-Cyclobutyl                                                     ##STR14##   3-CH.sub.2 OH-4,6-diCH.sub.3 3-CH.sub.2                                        OH-5,6-diCH.sub.3 4-CH.sub.2 OH-2,3-diCH.sub.3       4-CH.sub.2 OH-2,5-diCH.sub.3 4-CH.sub.2 OH-5,6-diCH.sub.3 3-CH.sub.2           OH-4,5,6-triCH.sub.3                                                                        2-CH.sub.2 CH(OH)CH.sub.3 -4-CH.sub.3 2-C(CH.sub.3).sub.2                      OH-4-CH.sub.3 3-C(CH.sub.3).sub.2 OH-6-CH.sub.3                                              ##STR15##                                           2-CH.sub.2 CH.sub.2 OH 3-CH.sub.2 CH.sub.2 OH                                               4-C(CH.sub.3).sub.2 OH-3-CH.sub.3 2-CH(CH.sub.3)OH-4-C.sub.2                   H.sub.5                                                                                      ##STR16##                                           4-CH.sub.2 CH.sub.2 OH                                                                      2-CH.sub.2 CH.sub.2 OH-5-C.sub.2 H.sub.5                                                    2,3-di-CH.sub.2 OH                                   2-CH.sub.2 CH.sub.2 OH-4-CH.sub.3                                                           3-CH(CH.sub.3)OH-2,5-diCH.sub.3                                                             2,5-di-CH.sub.2 OH                                   2-CH.sub.2 CH.sub.2 OH-3-CH.sub.3                                                           4-CH.sub.2 CH.sub.2 OH-3,5-diCH.sub.3                                                       2,4-di-CH.sub.2 OH                                   2-CH.sub.2 CH.sub.2 OH-5-CH.sub.3                                                           2-CH(C.sub.3 H.sub.7)OH                                                                     3,4-di-CH.sub.2 OH                                   3-CH.sub.2 CH.sub.2 OH-2-CH.sub.3                                                           3-CH(C.sub.3 H.sub.7)OH                                                                     3,5-di-CH.sub.2 OH                                   3-CH.sub.2 CH.sub.2 OH-4-CH.sub.3                                                           4-CH(C.sub.3 H.sub.7)OH                                                                     2-CH.sub.2 OH-3-OH                                   3-CH.sub.2 CH.sub.2 OH-5-CH.sub.3                                                           2-CH(C.sub.2 H.sub.5)CH.sub.2 OH                                                            2-CH.sub.2 OH-3-OH-6-CH.sub.3                        3-CH.sub.2 CH.sub.2 OH-6-CH.sub.3                                                           3-CH(C.sub.2 H.sub.5)CH.sub.2 OH                                                            2-CH-(CH.sub.2 OH).sub.2                             4-CH.sub.2 CH.sub.2 OH-3-CH.sub.3                                                           4-CH(C.sub.2 H.sub.5)CH.sub.2 OH                                                            3-CH(CH.sub.2 OH).sub.2                              4-CH.sub.2 CH.sub.2 OH-2-CH.sub.3                                                           2-CH.sub.2 (CH.sub.2).sub.3 OH                                                              4-CH(CH.sub.2 OH).sub.2                              2-CH(CH.sub.3)OH-3-CH.sub.3                                                                 3-CH.sub.2 (CH.sub.2).sub.3 OH                                                              3-C(CH.sub.2 OH).sub.3                               2-CH(CH.sub.3)OH-4-CH.sub.3                                                                 4-CH.sub.2 (CH.sub.2).sub.3 OH                                                              4-C(CH.sub.2 OH).sub.3                               2-CH(CH.sub.3)OH-5-CH.sub.3                                                                 2-CH(CH.sub.3)CH.sub.2 CH.sub.2 OH                                                          2-CHOHCH.sub.2 OH                                    3-CH(CH.sub.3)OH-2-CH.sub.3                                                                 3-CH(CH.sub.3)CH.sub.2 CH.sub.2 OH                                                          3-CHOHCH.sub.2 OH                                    3-CH(CH.sub.3)OH-4-CH.sub.3                                                                 4-CH(CH.sub.3)CH.sub.2 CH.sub.2 OH                                                          4-CHOHCH.sub.2 OH                                    3-CH(CH.sub.3)OH-5-CH.sub.3 3-CH(CH.sub.3)OH-6-CH.sub.3 4-CH(CH.sub.3)OH-2     -CH.sub.3                                                                                    ##STR17##   2-COCH.sub.2 OH 3-COCH.sub.2 OH 4-COCH.sub.2                                   OH                                                   4-CH(CH.sub.3)OH-3-CH.sub.3 2-CH(C.sub.2 H.sub.5)OH 3-CH(C.sub.2 H.sub.5)O                   ##STR18##                                                                                   ##STR19##                                           4-CH(C.sub.2 H.sub.5)OH                                                                      ##STR20##   3-CH.sub.2 COCH.sub.3 2-CH.sub.2 COCH.sub.3          2-CH(CH.sub.3)CH.sub.2 OH                                                                   2-CH.sub.2 C(CH.sub.3).sub.2 OH                                                             4-CH.sub.2 COCH.sub.3                                3-CH(CH.sub.3)CH.sub.2 OH 4-CH(CH.sub.3)CH.sub.2 OH 4-CH(CH.sub.3)CH.sub.2      OH-5-CH.sub.3                                                                              3-CH.sub.2 C(CH.sub.3).sub.2 OH 4-CH.sub.2 C(CH.sub.3).sub.2                   OH 4-C(CH.sub.2)CH.sub.2 OH                                                                  ##STR21##                                           2-(CH.sub.2).sub.3 OH 3-(CH.sub.2).sub.3 OH                                                 3-C(CH.sub.2)CH.sub.2 OH 2-C(CH.sub.2)CH.sub.2 OH                                            ##STR22##                                           4-(CH.sub.2).sub.3 OH 2-CH.sub.2 CH(OH)CH.sub.3                                             4-CH(OH)CHCH.sub.2 2-CH(OH)CHCH.sub.2                                                        ##STR23##                                           3-CH.sub.2 CH(OH)CH.sub.3 4-CH.sub.2 CH(OH)CH.sub.3                                         3-CH(OH)CHCH.sub.2 2-CH(OH)CH.sub.2 CHCH.sub.2                                               ##STR24##                                            ##STR25##   2-OCH.sub.3 2-OCH.sub.3                                                                     2-butoxy 3-butoxy                                     ##STR26##   2-OCH.sub.3 -3-CH.sub.3 2-OCH.sub.3 -4-CH.sub.3 2-OCH.sub.3                    -5-CH.sub.3  4-butoxy 4-butoxy-2-CH.sub.3 2-Isobutoxy              ##STR27##   3-OCH.sub.3 -2-CH.sub.3 3-OCH.sub.3 -4-CH.sub.3                                             3-Isobutoxy 4-Isobutoxy                               ##STR28##   3-OCH.sub.3 -5-CH.sub.3 3-OCH.sub.3 -6-CH.sub.3 4-OCH.sub.3                    -2-CH.sub.3  2-tert butoxy 3-tert butoxy 4-tert butoxy             ##STR29##   4-OCH.sub.3 -3-CH.sub.3 2-OC.sub.2 H.sub.5 3-OC.sub.2 H.sub.                   5            2-OCH.sub.2CHCH.sub.2 3-OCH.sub.2CHCH.sub.2                                    4-OCH.sub.2CHCH.sub.2                                 ##STR30##   4-OC.sub.2 H.sub.5 2-OC.sub.2 H.sub.5 -3-CH.sub.3 2-OC.sub.2                   H.sub.5 -4-CH.sub.3 2-OC.sub.2 H.sub.5 -5-CH.sub.3                                          2-OCH.sub.2 CH.sub.2 OH 3-OCH.sub.2 CH.sub.2 OH                                -OCH.sub.2 CH.sub.2 OH 2-CH.sub.2OCH.sub.3            ##STR31##   3-OC.sub.2 H.sub.5 -2-CH.sub.3 3-OC.sub.2 H.sub.5 -4-CH.sub.3                               3-CH.sub.2OCH.sub.3 3-CH.sub.2 OCH.sub.32CH.sub.                               3                                                     ##STR32##   3-OC.sub.2 H.sub.5 -5-CH.sub.3 3-OC.sub.2 H.sub.5 -6-CH.sub.3                               2-CH.sub.2 OC.sub.2 H.sub.5 3-CH.sub.2 OC.sub.2                                H.sub.5                                               ##STR33##   4-OC.sub.2 H.sub.5 -2-CH.sub.3 4-OC.sub.2 H.sub.5 -3-CH.sub.3                               4-CH.sub.2 OC.sub.2 H.sub.5 2-CH.sub. 2                                        OC.sub.3 H.sub.7                                      ##STR34##   2-OCH.sub.3 -4-C.sub.2 H.sub.5 4-OCH.sub.3 -2,5-diCH.sub.3                     2-OCH(CH.sub.3).sub.2                                                                       3-CH.sub.2 OC.sub.3 H.sub.7 4-CH.sub.2 OC.sub.3                                H.sub.7 2-CH.sub.2 OCH(CH.sub.3).sub.2               4-CH.sub.2 CHO                                                                              3-OCH(CH.sub.3).sub.2                                             3-CH.sub.2 CHO                                                                              4-OCH(CH.sub.3).sub.2                                             2-CH.sub.2 CHO                                                                              4-OCH(CH.sub.3).sub.2 -2-CH.sub.3                                  ##STR35##                                                                      ##STR36##                                                                      ##STR37##                                                                     3-CH.sub.2 OCH(CH.sub.3).sub.2                                                              3-OH-2-CH.sub.3                                                                             3-SOCH.sub.3                                         4-CH.sub.2 OCH(CH.sub.3).sub.2                                                              3-OH-4-CH.sub.3                                                                             4-SOCH.sub.3                                         2-CH.sub.2 OCH.sub.2 CHCH.sub.2                                                             3-OH-5-CH.sub.3                                                                             2-SO.sub.2 CH.sub.3                                  3-CH.sub.2 OCH.sub.2 CHCH.sub.2                                                             3-OH-6-CH.sub.3                                                                             3-SO.sub.2 CH.sub.3                                  4-CH.sub.2 OCH.sub.2 CHCH.sub.2                                                             3-OH-2-C.sub.2 H.sub.5 -5-CH.sub.3                                                          4-SO.sub.2 CH.sub.3                                  2-CH.sub.2 CH.sub.2 OCHCH.sub.2                                                             3-OH-5-C.sub.2 H.sub.5 -2-CH.sub.3                                                          2-SO.sub.2 H.sub.5                                   3-CH.sub.2 CH.sub.2 OCHCH.sub.2                                                             3-OH-2-HC(CH.sub.3).sub.2                                                                   3-SC.sub.2 H.sub.5                                   4-CH.sub.2 CH.sub.2 OCHCH.sub.2                                                             3-OH-2-CH.sub.2 CH.sub.2 CH.sub.3                                                           4-SC.sub.2 H.sub.5                                   2-CH.sub.2 CH.sub.2 OCH.sub.3                                                               3-OH-2-butyl 2-SOC.sub.2 H.sub.5                                  3-CH.sub.2 CH.sub.2 OCH.sub.3                                                               3-OH-2-secbutyl                                                                             3-SOC.sub.2 H.sub.5                                  4-CH.sub.2 CH.sub.2 OCH.sub.3                                                               3-OH-2-tert.butyl                                                                           4-SOC.sub.2 H.sub.5                                  3-CH.sub.2 CH.sub.2 OCH.sub.3 -4-CH.sub.3                                                   3-OH-4-butyl 2-SO.sub.2 C.sub.2 H.sub.5                           2-CH.sub.2 CH.sub.2 OC.sub.2 H.sub.5                                                        3-OH-5-sec.butyl                                                                            3-SO.sub.2 C.sub.2 H.sub.5                           3-CH.sub.2 CH.sub.2 OC.sub.2 H.sub.5                                                        3-OH-2,4,5-tri-CH.sub.3                                                                     4-SO.sub.2 C.sub.2 H.sub.5                           4-CH.sub.2 CH.sub.2 OC.sub.2 H.sub.5                                                        3-OH-4,5,6-tri-CH.sub.3                                                                     2-CH.sub.2 SCH.sub.3                                 2-CH(OCH.sub.3)CH.sub.3                                                                     3-OH-6-CHCH(CH.sub.3)                                                                       3-CH.sub.2 SCH.sub.3                                 3-CH(OCH.sub.3)CH.sub.3                                                                     3-OH-2-CHCH(CH.sub.3)                                                                       2-CH.sub.2 SOCH.sub.3                                4-CH(OCH.sub.3)CH.sub.3                                                                     3-OH-4-CH.sub.2 CHCH.sub.2                                                                  4-CH.sub.2 SOCH.sub.3                                2-CH(OC.sub.2 H.sub.5)CH.sub.3                                                              3-OH-2-Cl    2-CH.sub.2 SO.sub.2 CH.sub.3                         3-CH(OC.sub.2 H.sub.5)CH.sub.3                                                              3-OH-5-Cl    4-CH.sub.2 SO.sub.2 CH.sub.3                         4-CH(OC.sub.2 H.sub.5)CH.sub.3                                                              3-OH-6-Cl    2-CH.sub.2 SC.sub.2 H.sub.5                          2-(CH.sub.2).sub.3 OCH.sub.3                                                                3-OH-2-Br    3-CH.sub.2 SC.sub.2 H.sub.5                          3-(CH.sub.2).sub.3 OCH.sub.3                                                                2-CH.sub.2 OCH.sub.2 CH.sub.2 OH                                                            4-CH.sub.2 SC.sub.2 H.sub.5                          4-(CH.sub.2).sub.3 OCH.sub.3                                                                3-CH.sub.2 OCH.sub.2 CH.sub.2 OH                                                            2-CH.sub.2 SOC.sub.2 H.sub.5                          ##STR38##   4-CH.sub.2 OCH.sub.2 CH.sub.2 OH 2-(CH.sub.2).sub.2 OCH.sub.2                   CH.sub.2 OH 3-CH.sub.2 SOC.sub.2 H.sub.5 4-CH.sub.2                                        SOC.sub.2 H.sub.5                                     ##STR39##   3-(CH.sub.2).sub.2 OCH.sub.2 CH.sub.2 OH 4-(CH.sub.2).sub.2                    OCH.sub.2 CH.sub.2 OH                                                                       2-CH.sub.2 SO.sub.2 C.sub.2 H.sub.5 3-CH.sub.2                                 SO.sub.2 C.sub.2 H.sub.5                              ##STR40##   2-OH 2-OH-3-CH.sub.3                                                                        4-CH.sub.2 SO.sub.2 C.sub.2 H.sub.5 4-SCH.sub.2                                CH.sub.2 CH.sub.3                                    3-OH-2-C.sub.2 H.sub.5                                                                      2-OH-4-CH.sub.3                                                                             3-SOCH.sub.2 CH.sub.2 CH.sub.3                       3-OH-4-C.sub.2 H.sub.5                                                                      2-OH-5-CH.sub. 3                                                                            2-SO.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                3-OH-5-C.sub.2 H.sub.5                                                                      4-OH         2-SCH(CH.sub.3).sub.2                                3-OH-6-C.sub.2 H.sub.5                                                                      4-OH-2-CH.sub.3                                                                             3-SOCH(CH.sub.3).sub.2                               3-OH-2,4-di-CH.sub.3                                                                        4-OH-3-CH.sub.3                                                                             4-SO.sub.2 CH(CH.sub.3).sub.2                        3-OH-2,5-diCH.sub.3                                                                         3-SCH.sub.3  2-CH.sub.2 CH.sub.2 SCH.sub.3                        3-OH-4,5-diCH.sub.3                                                                         4-SCH.sub.3  3-CH.sub.2 CH.sub.2 SOCH.sub.3                       3-OH-4,6-diCH.sub.3                                                                         2-SOCH.sub.3 4-CH.sub.2 CH.sub.2 SO.sub.2 CH.sub.3                2-CH.sub.2 CH.sub.2 SOC.sub.2 H.sub.5                                                       2-CF.sub.3   6-CH.sub.2 OCH.sub.3 -3-Br                           3-CH.sub.2 CH.sub.2 SO.sub.2 C.sub.2 H.sub.5                                                3-CF.sub.3   2-CH.sub.2 OCH.sub.3 -3-Cl                           4-CH.sub.2 CH.sub.2 SC.sub.2 H.sub.5                                                        4-CF.sub.3   4-CH.sub.2 OCH.sub.3 -3-Cl                           2-SCH.sub.2 CH.sub.2 OH                                                                     3-J          5-CH.sub.2 OCH.sub.3 -3-Cl                           3-SCH.sub.2 CH.sub.2 OH                                                                     2-OCH.sub.3 -3-Br                                                                           6-CH.sub.2 OCH.sub.3 -3-Cl                           4-SCH.sub.2 CH.sub.2 OH                                                                     4-OCH.sub.3 -3-Br                                                                           2-CH.sub.2 OCH.sub.3 -3-F                            2-SOCH.sub.2 CH.sub.2 OH                                                                    5-OCH.sub.3 -3-Br                                                                           4-CH.sub.2 OCH.sub.3 -3-F                            3-SOCH.sub.2 CH.sub.2 OH                                                                    6-OCH.sub.3 -3-Br                                                                           5-CH.sub.2 OCH.sub.3 -3-F                            4-SOCH.sub.2 CH.sub.2 OH                                                                    2-OCH.sub.3 -3-Cl                                                                           6-CH.sub.2 OCH.sub.3 -3-F                            2-SO.sub.2 CH.sub.2 CH.sub.2 OH                                                             4-OCH.sub.3 -3-Cl                                                 3-SO.sub.2 CH.sub.2 CH.sub.2 OH                                                             5-OCH.sub.3 -3-Cl                                                 4-SO.sub.2 CH.sub.2 CH.sub.2 OH                                                             6-OCH.sub.3 -3-Cl                                                 2-SCH.sub.2CHCH.sub.2                                                                       2-OCH.sub.3 -3-F                                                  3-SOCH.sub.2 CHCH.sub.2                                                                     4-OCH.sub.3 -3-F                                                  4-SO.sub.2 CH.sub.2 CHCH.sub.2                                                              5-OCH.sub.3 -3-F                                                  2-SCHCHCH.sub.3                                                                             6-OCH.sub.3 -3-F                                                  3-SCHCHCH.sub.3                                                                             3-F-5-OH                                                          4-SCHCHCH.sub.3                                                                             3-Cl-5-OH                                                         4-CH.sub.2 SCH.sub.2 CHCH.sub.2                                                             3-Br-5-OH                                                                      3-J-5-OH                                                                       2-CH.sub.2 OH-3-Br                                                             4-CH.sub.2 OH-3-Br                                                             5-CH.sub.2 OH-3-Br                                                             6-CH.sub.2 OH-3-Br                                                             2-CH.sub.2 OH-3-Cl                                                             4-CH.sub.2 OH-3-Cl                                                             5-CH.sub.2 OH-3-Cl                                                             6-CH.sub.2 OH-3-Cl                                                             2-CH.sub.2 OH-3-F                                                              4-CH.sub.2 OH-3-F                                                              5-CH.sub.2 OH-3-F                                                              6-CH.sub.2 OH-3-F                                                              5-OC.sub.2 H.sub.5 -3-Br                                                       5-OC.sub.2 H.sub.5 -3-Cl                                                       5-OC.sub.2 H.sub.5 -3-F                                                        2-CH.sub.2 OCH.sub.3 -3-Br                                                     4-CH.sub.2 OCH.sub.3 -3-Br                                                     5-CH.sub.2 OCH.sub.3 -3-Br                                        __________________________________________________________________________

                                      TABLE 2                                      __________________________________________________________________________     A'                A'                 A'                                        __________________________________________________________________________      ##STR41##                                                                                        ##STR42##                                                                                         ##STR43##                                R = H             R = H              R = H                                     = 7-OH            = 8-CH.sub.3       4-OH                                      = 7-OCH.sub.3     = 8-OH             4-OCH.sub.3                               = 7-CH.sub.2 OH   = 8-OH, 3-CH.sub.3 1-Cl                                      = 7,7-diCH.sub.2 OH                                                                              = 8-CH.sub.2 OH    5-Cl                                      = 7-Cl            = 8-CH.sub.2 OH, 3-CH.sub.3                                  = 7-exo-methylene = 8-OCH.sub.3                                                = 7-CONH.sub.2 = 3-OH = 3-CH.sub.2 OH                                                            = 8,8-di-CH.sub.2 OH = 8-Cl = 8-Br                                                                 ##STR44##                                = 4-CH.sub.3      = 8-exo-methylene  R = H                                     = 4-CH.sub.2 OH   = 8-CONH.sub.2     = 4-OH                                    = 5-OH, 7-CH.sub.3                                                                               = 8-Oxo            = 4-OCH.sub.3                             = 6-OH, 7-CH.sub.3                                                                               = 6-Cl             = 1-Cl                                    = 5-CH.sub.3      = 5-OH             = 5-Cl                                    = 6-CH.sub.3      = 5-oxo                                                      = 7-CH.sub.3      = 5-Cl                                                        ##STR45##        = 3-CH.sub.2 OH = 3-OH = 4-OCH.sub.3                                                               ##STR46##                                 ##STR47##                                                                                        ##STR48##                                                    ##STR49##                                                                                        ##STR50##                                                                                         ##STR51##                                 ##STR52##                                                                                        ##STR53##                                                                                         ##STR54##                                 ##STR55##                                                                                        ##STR56##                                                                                         ##STR57##                                 ##STR58##                                                                                        ##STR59##                                                                                         ##STR60##                                 ##STR61##                                                                                        ##STR62##                                                                                         ##STR63##                                                   ##STR64##                                                    ##STR65##                                                                                        ##STR66##                                                    ##STR67##                                                                                        ##STR68##                                                   __________________________________________________________________________

The same compounds as in Tables 1 and 2 are obtained when in the general formula I the radical R² denotes C₂ H₅ instead of CH₃.

The illustrative examples below of syn compounds which can be prepared according to the invention serve to illustrate the invention in more detail but do not restrict it.

EXAMPLE 1: 7-[2-(2-Aminothiazol-4-yl)-2-syn-methoxyimino-acetamido]3-[(4-ethyl-1-pyridinium)-methyl]-ceph-3-em-4-carboxylate (Process a) Variant a

A mixture of 6.83 g (15 mmoles) of 7-[2-(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamido]-cephalosporanic acid, 1.38 g (16.5 mmoles) of sodium bicarbonate, 74.7 g (450 mmoles) of potassium iodide, 16.07 g (150 mmoles) of 4-ethylpyridine and 70 ml of water was stirred for 5 hours at 50°-55° C. During this period the pH was maintained at a value between 6.8 and 7.2 by the occasional addition of sodium bicarbonate. The mixture was diluted with 500 ml of acetone and chromatographed over silica gel (Merck 0.063-0.2 mm, 25×3 cm column). Potassium iodide is eluted with acetone/water (7:1) and thereafter the title compound is eluted with acetone/water (3:1). The freeze-dried crude product was rechromatographed over silica gel (Merck "Lobar" column C, about 1 bar, acetone/water 3:1). Freeze-drying of the product fractions produced 3.7 g of the title compound in the form of a colorless solid.

¹ H-NMR (CF₃ CO₂ D): δ=1.46 (t, J=7 Hz, 3H, CH₂ --CH₃); 3.07 (q, J=7 Hz, 2H, CH₂ --CH₃); 3.50 and 3.77 (AB, J=19 Hz, 2H, S-CH₂); 4.23 (s, 3H, OCH₃); 5.19-6.22 (m, 4H, CH₂ Py and 2 lactam-H); 7.37 (s, 1H, thiazole); 7.91 and 8.80 ppm (AA'BB', J=6 Hz, 4H, Py).

IR (KBr): 1,775 cm⁻¹ (lactam-CO).

Variant b

The title compound was obtained in the same purity as above and in a yield of 4.9 when 6.83 g (15 mmoles) of 7-[2-(2-(aminothiazol-4-yl)-2-syn-methoxyimino-acetamido]-cephalosporanic acid, 1.38 g (16.5 mmoles) of sodium bicarbonate, 4.8 g (45 mmoles) of 4-ethylpyridine, 31.5 g (210 mmoles) of sodium iodide and 21 ml of water were stirred for 110 hours at 25° C.

Variant c

Using the amounts of the components as described under variant b and a reaction time of 1 hour at 80° C., produced 4.5 g of the title compound in the form of a colorless solid.

Procedures analogous to Example 1 produced the compounds which are listed below, corresponding to the general formula I in which R¹ denotes hydrogen and R² denotes methyl, and carry, in the pyridinium radical (A in the formula I), the substitutents indicated in the second column of Table 3.

The numeral attached to the substituents indicates in each case the precise position of the substituent(s) in the pyridinium radical.

                                      TABLE 3                                      __________________________________________________________________________                      Yield                                                         Example                                                                              Substituent                                                                               % of theory                                                                            Comments      .sup.1 H-NMR: δ(ppm)              __________________________________________________________________________      2    3-C.sub.2 H.sub.5                                                                         61      Rechromatographed with acetone/water                                                          ##STR69##                               3    2-C.sub.2 H.sub.5                                                                         28      Rechromatographed with acetone/water                                                          ##STR70##                               4    4-CH.sub.2 CH.sub.2 CH.sub.3                                                              45      Rechromatographed with acetone/water                                                          ##STR71##                                                                     CH.sub.2 Py and 2 lactam H); 7.35                                              (s, 1H, thiazole); 7.86 and 8.78                                               (AA'BB', J=6Hz, 4H, Py)                  5    4-iso-C.sub.3 H.sub.7                                                                     47      Rechromatographed with                                                                       (F.sub.3 CCO.sub.2 D); 1.46(d,                                                 J=7Hz, 6H,                                                       acetone/water 4:1                                                                            iso-C.sub.3 H.sub.7); 2.97-4.07(m,                                             3H,                                                                            iso-C.sub.3 H.sub.7 and                                                        SCH.sub.2); 4.23(s,                                                            3H, OCH.sub.3); 5.17-6.23(m, 4H,                                               CH.sub.2Py                                                                     and 2 lactam-H); 7.37(s,                                                       1H, thiazole); 7.93 and 8.82                                                   (AA'BB', J=6Hz, 4H, Py)                  6    2-CH.sub.3 37      Rechromatography with                                                                        (F.sub.3 CCO.sub.2 D): 2.98(s, 3H                                              PyCH.sub.3);                                                     acetone/water (2:1)                                                                          3.52 and 3.71(AB, J=19Hz, 2H,                                                  SCH.sub.2);                                                      produced small amounts                                                                       4.24(s, 3H, OCH.sub.3); 5.35-                                    of the Δ2-isomer as a                                                                  6.12(m, 4H, CH.sub.2 Py and 2                                                  lactam-H);                                                       by-product.   7.37(s, 1H, thiazole); 7.79-8.76                                               (m, 4H, Py)                              7    4-t-C.sub.4 H.sub.9                                                                       41      Rechromatographed with                                                                       (F.sub.3 CCO.sub.2 D): 1.51(s, 9H,                                             C.sub.4 H.sub.9);                                                actone/water 2:1                                                                             3,48 and 3.79(AB, J=19Hz, 2H,                                                  SCH.sub.2); 4.23(s, 3H,                                                        OCH.sub.3),                                                                    5.16-6.21(m, 4H, CH.sub.2Py and                                                2-lactam-H); 7.36(s, 1H,                                                       thiazole);                                                                     8.07 and 8.82(AA'BB', J=7Hz,                                                   4H, Py)                                  8    3-CH.sub.3 -4-CH.sub.3                                                                    47      Rechromatographed                                                                            (F.sub.3 CCO.sub.2 D): 2.55(s, 3H,                                             CH.sub.3 Py);                                                    with acetone/water 2:1                                                                       2.66(s, 3H, CH.sub.3 Py); 3.47 and                                             3.74                                                                           (AB, J=19Hz, 2H, SCH.sub.2);                                                   4.22(s, 3H,                                                                    OCH.sub.3); 5.11-6.21(m, 4H,                                                   CH.sub.2Py                                                                     and 2 lactam-H); 7.35 (s, 1H,                                                  thiazole); 7.76-8.61(m, 3H, Py)          9    3-CH.sub.3 -5-CH.sub.3                                                                    51                    (F.sub.3 CCO.sub.2 D): 2.62(s, 6H,                                             CH.sub.3 Py);                                                                  3.47 and 3.74(AB, J=19Hz, 2H,                                                  SCH.sub.2); 4.22(s, 3H, OCH.sub.3)                                             5.14-                                                                          6.27(m, 4H, CH.sub.2Py and 2                                                   lactam-                                                                        H); 7.36(s, 1H, thiazole); 8.18-                                               8.57(m, 3H, Py)                         10    3-C.sub.2 H.sub.5 -4-CH.sub.3                                                             38      Rechromatographed with acetone/water                                                          ##STR72##                              11    3-C.sub.2 H.sub.5 -6-CH.sub.3                                                             22      Rechromatographed with acetone/water                                                          ##STR73##                              12    2-CH.sub.2 C.sub.6 H.sub.5                                                                11      Rechromatographed with acetone/water                                                          ##STR74##                                                                     Lactam-H); 7.03-7.77(m, 6H,                                                    thiazole and C.sub.6 H.sub.5);                                                 7.77-8.83                                                                      (m, 4H, Py)                             13    4-C.sub. 6 H.sub.5                                                                        12      Rechromatographed with                                                                       (F.sub.3 CCO.sub.2 D): 3.55 and                                                3.82(AB,                                                         acetone/water 4:1                                                                            J=19Hz, 2H, SCH.sub.2); 4.20(s,                                                3H,                                                                            OCH.sub.3); 5.20-6.26(m, 4H,                                                   CH.sub.2Py                                                                     and 2 lactam-H); 7.35(s, 1H,                                                   thiazole) 7.51-7.89(m, 5H, C.sub.6                                             H.sub.5);                                                                      8.26 and 8.91(AA'BB', J=7Hz, 4H,                                               Py)                                     14    2-CH.sub.2 OH                                                                             38                                                                                                    ##STR75##                              15    3-CH.sub.2 OH                                                                             58      Reaction time: 8 days                                                                        (CF.sub.3 COOD): 3.54 and 3.79                                                 (AB,                                                             at 25° C.                                                                             J=18Hz, 2H, SCH.sub.2); 4.22(s,                                                3H,                                                                            OCH.sub.3), 5.17(s, 2H, CH.sub.2                                               OH), 5.14-                                                                     6.32(m, 4H, CH.sub.2 Py+2                                                      lactam-H);                                                                     7,38(s, 1H, thiazole); 7.95-9.10                                               (m, 4H, Py)                             16    3-OH       47      Rechromatographed over                                                                       (D.sub.2 O): 3.21 and 3.45(AB,                                                 J=17Hz,                                                          XAD-2 with water                                                                             2H, CH.sub.2 S); 3.93(s, 3H,                                                   OCH.sub.3); 5.35-                                                              5.85(m, 4H, CH.sub.2Py and 2                                                   lactam-                                                                        H); 6.93(s, 1H, thiazole); 7.43-                                               7.95(m, 4H, Py)                         17                                                                                    ##STR76## 35      Reaction time: 110 hours at 23° C. + 2                                  hours at 50° C.                                                                        ##STR77##                              18                                                                                    ##STR78## 67      Reaction time: 110 hours at 23° C. + 2                                  hours at 50° C. Obtained pure after 1st                                 chromato- graphy.                                                                             ##STR79##                              19    4-CH(CH.sub.3)OH                                                                          64      Rechromatographed with acetone/water                                                          ##STR80##                              20    3-C(CH.sub.3).sub.2 OH                                                                    58      Rechromatographed with                                                                       (F.sub.3 CCO.sub.2 D): 1.83(s, 6H,                                             CH.sub.3);                                                       acetone/water 4:1                                                                            3.54 and 3.78(AB, J=20Hz, 2H,                                                  SCH.sub.2); 4.21(s, 3H,                                                        OCH.sub.3);                                                                    5.33-6.28(m, 4H, CH.sub.2Py and                                                2 lactam-H; 7.36(s, 1H, thiazole)                                              7.96-9.26(m, 4H, Py)                    21    4-C(CH.sub.3).sub.2 OH                                                                    56      Rechromatographed with                                                                       (F.sub.3 CCO.sub.2 D): 1.83(s, 6H,                                             CH.sub.3);                                                       acetone/water 4:1                                                                            3.51 and 3.81(AB, J=19Hz, 2H,                                                  SCH.sub.2); 4.23(s, 3H,                                                        OCH.sub.3);                                                                    5.23-6.24(m, 4H, CH.sub.2Py and                                                2 lactam-H); 7.36(s, 1H,                                                       thiazole);                                                                     8.21 and 8.92(AA'BB', J=7Hz, 4H,                                               Py)                                     22    3-CH.sub.2 CH.sub.2 CH.sub.2 OH                                                           38      Rechromatographed with                                                                       (F.sub.3 CCO.sub.2 D): 2.17(m, 2H,                                             propyl),                                                         acetone/H.sub.2 O 4:1,                                                                       2.90-4.25(m, 6H, SCH.sub.2 and                                   reaction time 3 days at                                                                      4 propyl-H) 4.22(s, 3H,                                                        OCH.sub.3);                                                      23° C. + 2 hours at 50° C.                                                     5.20-6.88(m, 4H, CH.sub.2 Py and                                               2 lactam-H); 7.36(s, 1H,                                                       thiazole);                                                                     7.90-8.86(m, 4H, Py)                    23    3-COCH.sub.3                                                                              47      Rechromatographed over                                                                       (F.sub.3 CCO.sub.2 D): 2.91(s, 3H,                                             Ac); 3.61                                                        XAD-2 (column 10 × 2 cm)                                                               and 3.86(AB, J=19Hz, 2H,                                                       SCH.sub.2);                                                      with methanol/water 4:1                                                                      4.24(s, 3H, OCH.sub.3),                                                        5.34-6.39(m,                                                                   4H, CH.sub.2 Py and 2 lactam-H),                                               7.36                                                                           (s, 1H, thiazole, 8.17-9.60(m,                                                 4H,                                                                            Py)                                     24    3-COC.sub.6 H.sub.5                                                                       18                    (F.sub.3 CCO.sub.2 D): 3.64 and                                                3.87(AB,                                                                       J=19Hz, 2H, SCH.sub.2); 4.23(s,                                                3H,                                                                            OCH.sub.3); 5.35-6.42(m, 4H,                                                   CH.sub.2 Py and                                                                2 lactam-H); 7.37-9.45(m, 10H,                                                 thiazole, (C.sub.6 H.sub.5 and                                                 Py)                                     25    4-COC.sub.6 H.sub.5                                                                       21      Rechromatographed over                                                                       (F.sub.3 CCO.sub.2 D): 3.62 and                                                3.87(AB,                                                         XAD-2 with methanol/                                                                         J=19Hz, 2H, SCH.sub.2); 4.23(s,                                                3H,                                                              water 4:1     OCH.sub.3); 5.35-6.41(m, 4H,                                                   CH.sub.2Py                                                                     and 2 lactam-H); 7.37-9.26(m,                                                  10H, thiazole, C.sub.6 H.sub.5 and                                             Py)                                     26    4-OCH.sub.3                                                                               45                    (CF.sub.3 COOD): 3.48 and                                                      3.72(AB,                                                                       J=18Hz, 2H, SCH.sub.2); 4.20(s,                                                3H,                                                                            OCH.sub.3); 4.23(s, 3H,                                                        OCH.sub.3); 5.03-                                                              6.10(m, 4H, CH.sub.2Py and 2                                                   lactam-                                                                        H); 7.36-7.48(3H, thiazole-H,                                                  2 PyH); 8.62-8.75(AA'BB',                                                      J=7Hz, 2H, Py)                          27    4-CH.sub.2 OCH.sub.3                                                                      57      Rechromatographed over XAD-2 with                                                             ##STR81##                              28    2-SCH.sub.3                                                                               14                    (CF.sub.3 COOD): 2.91(s, 3H                                                    SCH.sub.3);                                                                    3.52 and 3.74(AB, J=18Hz, 2H,                                                  SCH.sub.2); 4.24(s, 3H,                                                        OCH.sub.3);                                                                    5.25-6.55(m, 4H, CH.sub.2 Py -                                                 2lactam-                                                                       H); 7.36(s, 1H, thiazole); 7.55-                                               8.80(m, 4H, Py)                         29    4-CH.sub.2 SCH.sub.3                                                                      25                    (CF.sub.3 COOD): 2.14(s, 3H,                                                   CH.sub.3 );                                                                    3.47 and 3.80(AB, J=18Hz, 2H,                                                  SCH.sub.2); 3.94(s, 2H, CH.sub.2                                               S); 4.20                                                                       (s, 3H, OCH.sub.3); 5.18-6.20(m,                                               4H,                                                                            CH.sub.2Py and 2 lactam-H); 7.35                                               (s, 1H, thiazole); 8.15 and 8.85                                               (AA'BB', J=6Hz, 4H, Py)                 30    3-CH.sub.2 SOCH.sub.3                                                                     12      Rechromatographed with                                                                       (CF.sub.3 COOD): 3.01(s, 3H,                                                   SOCH.sub.3);                                                     acetone/water 4:1                                                                            3.60 and 3.81(AB, 2H, SCH.sub.2);                                              4.24(s, 3H, OCH.sub.3); 4.57(s,                                                2H,                                                                            CH.sub.2 SO); 5.25-6.58(m, 4H,                                                 CH.sub.2Py                                                                     and 2 lactam-H); 7.34(s, 1H,                                                   thiazole); 8.05-9.10(m, 4H, Py)         31    3-CH.sub.2 SO.sub.2 CH.sub.3                                                              23                    (CF.sub.3 COOD); 3.34(s, 3H,                                                   SO.sub.2 CH.sub.3);                                                            3.62 and 3.82(AB, 2H, SCH.sub.2);                                              4.23(s, 3H, OCH.sub.3); 4.88(s,                                                2H,                                                                            CH.sub.2 SO.sub.2); 5.30-6.35(m,                                               4H, CH.sub.2Py                                                                 and 2 lactam-H); 7.35(s,                                                       1H, thiazole); 8.05-9.18(m, 4H,                                                Py)                                     32    3-F        45      Rechromatographed with                                                                       (D.sub.6 -DMSO): 3.76(s, 3H,                                                   OCH.sub.3);                                                      methanol/water 4:1                                                                           4.52-5.96(m, 4H, CH.sub.2Py and 2                                              lactam-H);                                                                     6.63(s, 1H, thiazole); 7.10                                                    (bs, 2H, NH.sub.2); 7.80-9.86(m,                                               5H, Py and NH)                          33    4-NHCOCH.sub.3                                                                            22                    (CF.sub.3 COOD): 2.46(s, 3H,                                                   COCH.sub.3);                                                                   3.47 and 3.80(AB, J=18Hz, 2H,                                                  SCH.sub.2);                                                                    4,21(s, 3H, OCH.sub.3); 5.12-                                                  6.35(m, 4H CH.sub.2Py and 2                                                    lactam-H);                                                                     7.35(s, 1H thiazole); 8.26 and                                                 8.73 (AA'BB', J=6Hz, 4H, Py)            34                                                                                    ##STR82## 28      Variant b, 20% of acetone added to the reaction                                meduim        (CF.sub.3 COOD): 3.60 and 3.87(AB,                                             = 18Hz, 2H, SCH.sub.2); 4.20(s,                                                3H, OCH.sub.3); 5.28-6.38(AB, 3H,                                              CH.sub.2Py); 5.37(d, J=5Hz,                                                    C.sub.6 -lactam-H); 6.08 (d,                                                   J=5Hz, C.sub.7 -lactam-H); 7.38(s,                                             H, thiazole); 8.15-9.41(m, 8H, Py                                              )                                       35                                                                                    ##STR83## 57      Rechromatographed with acetone/water                                                         (D.sub.2 O): 3.33 and 3.63(AB,                                                 J=18Hz, 2H, SCH.sub.2); 3.86(s,                                                3H, OCH.sub.3); 5.05-5.76(m, 4H,                                               CH.sub.2Py and 2 lactam-H);                                                    6.76(s, 1H, thiazole); 6,53-6,80;                                              8.08-8.38; 9.00-9.15 (8H, Py)           36    3-CO.sub.2 C.sub.2 H.sub.5                                                                27      Rechromatographed over XAD-2 with                                                             ##STR84##                              37    4-CO.sub.2 C.sub.2 H.sub.5                                                                48                                                                                                    ##STR85##                              38    3-CH.sub.2CO.sub.2 H                                                                      19      Rechromatographed with acetone/water                                                          ##STR86##                              39    3-CH.sub.2 CO.sub.2 C.sub.2 H.sub.5                                                       47      Rechromatographed with acetone/water                                                          ##STR87##                              40    4-CONHCONHC.sub.2 H.sub.5                                                                 28      Rechromatographed with acetone/water                                                          ##STR88##                              41    4-CH.sub.2 CONH.sub.2                                                                     43                    (D.sub.2 O): 3.23 and 3.53(AB,                                                 J=18Hz,                                                                        2H, SCH.sub.2); 3.93(s, 3H,                                                    OCH.sub.3);                                                                    5.22(d, 1H, J=5Hz, C.sub.6                                                     -lactam-H);                                                                    5.31 and 5.44(AB, 2H,                                                          CH.sub.2Py);                                                                   5.81(d, 1H, J=5Hz, C.sub.7                                                     -lactam-H);                                                                    6.92(s, 1H, thiazole); 7.93 and                                                8.80(AA'BB', J=6Hz, 4H, Py)             42    3-CONH.sub.2                                                                              47                    (CF.sub.3 COOD): 3.60 and                                                      3.83(AB,                                                                       J=18Hz, 2H, SCH.sub.2); 4.22(s,                                                3H,                                                                            OCH.sub.3); 5.33-6.38(m, 4H,                                                   CH.sub.2Py                                                                     and 2 lactam-H); 7.36(s, 1H,                                                   thiazole); 8.12-9.60(m, 4H, Py)         43    3-CONHCO.sub.2 C.sub.2 H.sub.5                                                            17                                                                                                    ##STR89##                              44    4-CONHCO.sub.2 C.sub.2 H.sub.5                                                            19                                                                                                    ##STR90##                              45    4-CONHC.sub.2 H.sub.5                                                                     43                                                                                                    ##STR91##                              46    3-CON(C.sub.2 H.sub.5).sub.2                                                              36                    (CF.sub.3 COOD): 1.22-1.53(m, 6H,                                              C.sub.2 H.sub.5);                                                              3.15-4.25(m, 6H, SCH.sub.2 and                                                 C.sub.2 H.sub.5);                                                              4.25(s, 3H, OCH.sub.3); 5.35-6.40                                              (m, 4H, CH.sub.2Py and                                                         2-lactam-H);                                                                   7.41(s, 1H, thiazole); 8.10-                                                   9.22(m, 4H, Py)                         47    4-CN       31                    (D.sub.2 O): 3.22 and 3.42(AB,                                                 J=17Hz,                                                                        2H, SCH.sub.2); 3.93(s, 3H,                                                    OCH.sub.3);                                                                    5.15-5.92(m, 4H, CH.sub.2Py and                                                2 lactam-H); 6.93(s, 1H,                                                       thiazole)                                                                      8.25-9.28(AA'BB', 4H, Py)               48    4-SO.sub.2 NH.sub.2                                                                       26      Rechromatographed                                                                            (CF.sub.3 COOD): 3.55 and                                                      3.82(AB,                                                         over XAD-2 with                                                                              J=19Hz, 2H, SCH.sub.2); 4.23(s,                                                3H,                                                              water         OCH.sub.3); 5.30-6.33(m, 4H,                                                   CH.sub.2Py                                                                     and 2 lactam-H); 7.40(s, 1H,                                                   thiazole); 8.65 and 9.15(AA'BB',                                               J=7Hz, 4H, Py)                          49    4-CH.sub.2 CH.sub.2 SO.sub.3 K                                                            42      Rechromatographed over                                                                       (D.sub.6 -DMSO): 2.30-4.05(m, 6H,                                HP 20 adsorption resin,                                                                      SCH.sub.2 and CH.sub.2CH.sub.2);                                               3.75(s,                                                          Mitsubishi Co.                                                                               3H, OCH.sub.3); 4.75-5.72(m, 4H,                                               CH.sub.2Py                                                                     and 2 lactam-H); 6.63(s, 1H,                                                   thiazole) 7.12(bs, 2H, NH.sub.2);                                              7.96 and 9.25 (AA'BB', J=7Hz,                                                  4H, Py); 9.45(d, J=8Hz,                 __________________________________________________________________________                                            NH)                                

A procedure analogous to Example 1, variant b, produced the compounds which are listed below, correspond to the general formula I in which R¹ denotes hydrogen and R² denotes methyl, and carry the substituent indicated in the second column of Table 4 as the radical A.

                                      TABLE 4                                      __________________________________________________________________________                    Yield                                                           Example                                                                             A         % of theory                                                                           Comments     .sup.1 H-NMR: δ (ppm)                 __________________________________________________________________________     50                                                                                   ##STR92##                                                                               48     Rechromatographed with acetone/water 4:1 Reaction                              time: 3 days at 23° C. and 2 hours at                                   50° C. with 30% of ace- tone added to the                               reaction medium                                                                             (CF.sub.3 COOD): 2.40-2.70(m, 2H,                                              cyclopentene-H); 3.22-4.23 (m, 6H,                                             4-cyclopentene-H and SCH.sub.2);                                               4.23(s, 3H, OCH.sub.3); 5.28-6.36 (m,                                          4H, CH.sub.2Py and 2 lactam-H);                                                7.37(s, 1H, thiazole); 7.66-8.58(m,                                            4H, Py)                                     51                                                                                   ##STR93##                                                                               38     Rechromatographed with acetone/water 4:1 Reaction                              time: 3 days at 23° C. and 2 hours at                                   50° C. with 30% of ace- tone added to the                               reaction medium                                                                             (CF.sub.3 COOD): 2.10(m, 4H, cyclo-                                            hexene-H); 3.18(m, 4H,                                                         cyclo- hexene-H); 3.50 and 3.70(AB,                                            J=19Hz, 2H, SCH.sub.2); 4.25(s, 3H,                                            OCH.sub.3); 5.38(d, J=5Hz, C.sub.6 -                                           lactam-H); 5.55 and 3.80(AB, 2H,                                               CH.sub.2Py); 6.08(d, J=5Hz, C.sub.7 -                                          lactam-H); 7.39(s, 1H, thiazole);                                              7.65-8.58(m, 3H, Py)                        __________________________________________________________________________

EXAMPLE 52 7-[2-(2-Aminothiazol-4-yl)-2-syn-ethoxyimino-acetamido]-3-(1-pyridiniummethyl)-ceph-3-em-3-carboxylate

A mixture of 7.25 g (15 mmoles) of 7-[2-(2-aminothiazol-4-yl)-2-syn-ethoxyimino-acetamido]-cephalosporanic acid, 1.38 g (16.5 mmoles) of sodium bicarbonate, 41.5 g (250 mmoles) of potassium iodide, 5.92 g (75 mmoles) of pyridine and 20 ml of water was stirred for 5 hours at 60° C. The residue obtained after freeze-drying was taken up in a little acetone/water and chromatographed over silica gel (Merck 0.063-0.2 mm, 40×4 cm column). Potassium iodide was eluted with acetone/water (20:1) and thereafter the title compound was eluted with acetone/water (4:1). The crude product was chromatographed over silica gel (Merck "Lobar" column, about 1 bar, acetone/water 4:1). Freeze-drying the product fractions produced 3.4 g of the title compound in the form of a colorless solid.

¹ H-NMR (D₆ -DMSO): δ=1.21 (t,J=7 Hz,3H,CH₂ --CH₃); 4.08 (q,J=7 Hz,2H,CH₂ --CH₃); 4.85-5.73 (m,4H,CH₂ Py and 2 lactam-H); 6.65 (s,1H, thiazole), 7.12 (bs,2H,H₂ N-thiazole); 8.08-9.47 ppm (m, 6H,Py and amide).

IR (KBr): 1775 cm⁻¹ (lactam-CO).

The following compounds were prepared analogously to Example 52.

EXAMPLE 53 7-[2-(2-Aminothiazol-4-yl)-2-syn-ethoxyimino-acetamido]-3-[(3-methyl-1-pyridinium)-methyl]-ceph-3-em-4-carboxylate

Colorless solid, yield 47% of theory.

¹ H-NMR (D₆ -DMSO): δ=1.19 (t,J=7 Hz,3H,CH₂ --CH₃); 2.48 (m,DMSO and Pv-CH₃); 3.29 (bs,H₂ O+S--CH₂); 4.08 (q,J=7 Hz,2H,CH₂ --CH₃); 4.85-5.71 (m,4H,CH₂ Py and 2 lactam-H); 6.63 (s,1H, thiazole); 7.08 (bs,2H,H₂ N-thiazole); 7.85-9.46 ppm (m,5H,Py and amide).

EXAMPLE 54 7-[2-(2-Aminothiazol-4-yl)-2-syn-ethoxyimino-acetamido]-3-[(4-hydroxymethyl-1-pyridinium)-methyl]-ceph-3-em-4-carboxylate

Colorless solid, yield 52% of theory.

¹ H-NMR (D₆ -DMSO): δ=1.21 (t,J=7 Hz,3H,CH₂ --CH₃); 3.31 (bs,H₂ O+S--CH₂); 4.10-5.72 (m,9H,CH₂ CH₃,CH₂ OH, CH₂ Py and 2 lactam-H); 6.63 (s,1H,thiazole); 6.9-7.3 (m, 3H,H₂ N and 1 Py-H); 7.92-9.45 (m,4H,3Py-H and amide).

EXAMPLE 55 7-[2-(2-Amino-5-chlorothiazol-4-yl)-2-syn-methoxyimino-acetamido]-3-[(2-methyl-1-pyridinium)-methyl]-ceph-3-em-4-carboxylate

A mixture of 0.98 g (2 mmoles) of 7-[2-(2-amino-5-chlorothiazol-4-yl)-2-syn-methoxyimino-acetamido]cephalosporanic acid, 0.18 g (2.2 mmoles) of sodium bicarbonate, 6.6 g (40 mmoles) of potassium iodide, 1.8 g (20 mmoles) of 2-picoline and 8 ml of water was stirred for 5 hours at 60° C. During this period the pH was maintained at a value between 6.5 and 7 by the occasional addition of sodium bicarbonate. The mixture was diluted with 70 ml of acetone and chromatographed over silica gel (Merck 0.063-0.2 mm, column 10×2 cm). Potassium iodide was eluted with acetone/water (7:1) and thereafter the title compound was eluted with acetone/water (3:1). The crude product (0.2 g) was rechromatographed over silica gel (Merck "Lobar" column B, about 1 bar, acetone/water 3:1). Freeze-drying the product fractions produced 0.13 g of the desired compound in the form of a colorless solid and small amounts of the Δ2-isomer.

¹ H-NMR (CF₃ CO₂ D): δ=2.98 (s,3H,Py-CH₃); 3.51 and 3.74 (AB,J=19 Hz, 2H,S--CH₂); 4.20 (s,3H,OCH₃); 5.34-6.11 (m,4H,CH₂ -Py and 2 lactam-H); 7.77-8.73 ppm (m,4H,Py).

IR (KBr): 1770 cm⁻¹ (lactam-CO).

The following compound was prepared analogously to Example 55.

EXAMPLE 56 7-[2-(2-Amino-5-chlorothiazol-4-yl)-2-syn-methoxyiminoacetamido]-3-[(4-methyl-1-pyridinium)-methyl]-ceph-3-em-4-carboxylate

¹ H-NMR: (CF₃ CO₂ D): δ=2.75 (s,3H,Py-CH₃); 3.49 and 3.77 (AB,J=19 Hz, 2H,S--CH₂); 4.19 (s,3H,OCH₃); 5.16-6.20 (m,4H,CH₂ -Py and 2 lactam-H); 7.86 and 8.76 ppm (AA'BB', J=6 Hz,4H,Py).

Comment: Rechromatography produced small amounts of the Δ2-isomer.

EXAMPLE 57 7-[2-(2-Aminothiazol-4-yl)-2-syn-methoxyimino-acetamido]-3-[(4-ethyl-1-pyridinium)-methyl]-ceph-3-em-4-carboxylate Process b)

a) 7-tert.-Butoxycarbonylaminocephalosporanic acid

A mixture of 12.8 g (50 mmoles) of 7-aminocephalosporanic acid, 20.3 g (0.1 mole) of bis-trimethylsilyl acetamide, 22 g (0.1 mole) of di-tert.-butyl dicarbonate and 150 ml of methylene chloride was left for 10 days at room temperature. The solution was then stirred for 3 hours after the addition of 200 ml of ice water. Unconverted 7-aminocephalosporanic acid was filtered off with suction, the organic phase of the filtrate was separated off, and the aqueous phase was extracted twice more with methylene chloride. The organic phase was washed several times with water and dried with magnesium sulfate. After the solvent had evaporated, 11 g (59% of theory) of an amorphous yellowish product remained.

NMR (D₆ -DMSO): δ=1.41 (s,9H,tert-butyl); 2.00 (s,3H,acetyl); 2.8-3.61 3.6 (2H,SCH₂ +H₂ O); 4.5-5.07 (m,3H,C₆ -lactam-H) and CH₂ OAc); 5.41 (dd,J=4.5 and 9 Hz,C₇ -lactam-H); 7.9 ppm (d,J=9 Hz;NH).

IR (KBr): 1785 (lactam-CO), 1725 cm⁻¹ (ester).

b) 7-tert.-Butoxycarbonylamino-3-[(4-ethyl-1-pyridinium)-methyl]-ceph-3-em-4-carboxylate

A mixture of 7.44 g (20 mmoles) of 7-tert.-butoxy-carbonylaminocephalosporanic acid, 66 g (0.4 mole) of potassium iodide, 15 g (0.14 mole) of 4-ethylpyridine and 30 ml of water was stirred for 6 hours at 75° C. The mixture was chromatographed over silica gel in a manner analogous to Example 1. The title compound was eluted with acetone/water (3:1). Yield: 2.4 g (30% of theory) of an amorphous product, after freeze-drying.

NMR (D₆ -DMSO): δ=1.05-1.48 (s,t,9H,tert.-butyl and 3H,CH₂ CH₃); 2.7-3.72 (2H,SCH₂ and H₂ O); 4.02-5.62 (m,6H,CH₂ CH₃, 2 lactam-H and CH₂ N); 7.63-9.44 ppm (m,5H,NH and 4Py-H).

IR (KBr): 1780 (lactam-CO), 1710 cm⁻¹ (ester).

c) 7-Amino-3-[(4-ethyl-1-pyridinium)-methyl]-ceph-3-em-4-carboxylate

A solution of 2.10 g (5 mmoles) of 7-tert.butoxycarbonylamino-3-[(4-ethyl-1-pyridinium)-methyl]-ceph-3-em-4-carboxylate in 20 ml of trifluoroacetic acid and 0.2 ml of anisole was left for 30 minutes at 10°-20° C. After trifluoroacetic acid had been distilled off, crystallization was induced in the residue by repeatedly triturating it with ether. The crystals were dissolved in 5 ml of water with the aid of sodium bicarbonate and the solution was chromatographed with water over a Servachrom XAD-2 adsorbent resin (2×40 cm column). The title compound was eluted after a forerun of 400 ml. The product fractions were freeze-dried, and 1.65 g (78% of theory) of a colorless solid were obtained.

NMR (CF₃ COOD): δ=1.47 (t,J=7 Hz,3H,CH₂ CH₃); 3.03 (q,J=7 Hz,2H,CH₂ CH₃); 3.60 and 3.78 (AB,J=19 Hz, 2H,SCH₂), 5.25-5.72 (m,4H, 2 lactam-H and 5.25 CH₂ N), 7.75 and 8.63 ppm (AA'BB',J=6 Hz,4Py-H).

IR (KBr): 1785 cm⁻¹ (lactam-CO).

d) 7-[2-(2-Aminothiazol-4-yl)-2-syn-methoxyiminoacetamido]-3-[(4-ethyl-1-pyridinium)-methyl]-ceph-3-em-4-carboxylate

1 g (5 mmoles) of 2-(2-amino-1,3-thiazol-4-yl)-2-syn-methoxyiminoacetic acid was suspended in 20 ml of methylene chloride. After the addition of 0.93 ml (10 mmoles) of N,N-dimethylacetamide, the mixture was cooled down to -5°, and a solution of 0.75 g (7.5 mmoles) of phosgene in 5 ml of toluene was added dropwise with stirring. The resulting mixture was stirred for 2 hours at -5° C., and after the mixture had been cooled down to -10° C. a cooled mixture at -10° C. of 1.60 g (3.8 mmoles) of 7-amino-3-[(4-ethyl-1-pyridinium)-methyl]-ceph-3-em-4-carboxylate, 1.1 ml (8 mmoles) of triethylamine, 2 g (10 mmoles) of bis-trimethylsilylacetamide and 20 ml of N,N-dimethylacetamide was added. The resulting mixture was stirred for 2 hours at -10° C., 30 ml of ice water were added, and stirring was continued for a further 30 minutes at 0°-5° C. and for 1 hour without cooling. The solvent was removed in vacuo, and the residue was chromatographed over silica gel with acetone/water (3:1) in a manner analogous to Example 1. Freeze-drying produced the title compound in a yield of 60%. The compound was in all respects identical to the compound of Example 1.

EXAMPLES 58-107

The compounds of Tables 3 and 4 were prepared from the corresponding 7-amino-ceph-3-em-4-carboxylate derivatives (general formula III, prepared analogously to Example 57 b and c) and 2-(2-amino-1,3-thiazol-4-yl)-2-syn-methoxyiminoacetic acid in a manner analogous to Example 57 d. The compounds were identical in all respects to those of Tables 3 and 4.

EXAMPLE 108 3-[(4-Cyclopropyl-1-pyridinium)-methyl]-7-[2-syn-methoxyimino-2-(2-aminothiazol-4-yl)-acetamido]-ceph-3-em-4-carboxylate (Process a)

The pH of a mixture of 4.55 g (10 mmoles) of 7-[(2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamido]cephalosporanic acid, 1 g (10 mmoles) of potassium bicarbonate and 2.38 g (20 mmoles) of 4-cyclopropylpyridine in 25 ml of water was adjusted by the addition of 1.5 ml of 2N acetic acid to a value of 6.5 and the mixture was then heated for 3 hours with stirring at 60°-63° C. After the batch had cooled down, it was diluted with 50 ml of acetone and chromatographed over 400 g of silica gel (Merck 0.063-0.2 mm) with acetone/water (2:1). After a forerun of 800 ml, the title compound was eluted. The freeze-dried crude product was rechromatographed over a "Lobar C" column (Merck) with acetone/water (2:1). Freeze-drying the product fractions produced 1 g (19.5% of theory) of a colorless amorphous solid.

¹ H-NMR (CF₃ CO₂ D): δ=1.17-2.51 (m, 5H, cyclopropyl); 3.48 and 3.76 (AB,J=19 Hz, 2H, SCH₂); 4.24 (s, 3H, OCH₃); 5.12-6.19 (m, 4H, CH₂ Py and 2 lactam-H); 7.41 (s, 1H, thiazole); 7.65 and 8.68 ppm (AA'BB', J=7 Hz, 4H, Py).

(Process b)

A mixture of 5 g (25 mmoles) of 2-(2-amino-1,3-thiazol-4-yl)-2-syn-methoxyiminoacetic acid, 3.8 g (25 mmoles) of 1-hydroxy-1H-benzotriazole hydrate, 5.7 g (27.5 mmoles) of dicyclohexylcarbodiimide and 125 ml of N,N-dimethylformamide was stirred for 3 hours at room temperature. The mixture was filtered and the filtrate was cooled down to 0° C. and added to a solution of 10.1 g (25 mmoles) of 7-amino-3-[(4-cyclopropyl-1-pyridinium)-methyl]-ceph-3-em-4-carboxylate dihydrochloride, 50 ml of N,N-dimethylformamide and 8 ml (63.5 mmoles) of N,N-dimethylaniline. The mixture was left overnight at room temperature, the precipitate was filtered off with suction, and the filtrate was added dropwise with stirring to 1.5 l of diethyl ether. The amorphous precipitate was stirred together with acetone, filtered off with suction and washed with acetone. This crude product was dissolved in 200 ml of water, a small amount of undissolved material was filtered off, and the aqueous solution was freeze-dried. 8.8 g (68% of theory) of a colorless solid were obtained. The compound was in all respects identical to the compound obtained above according to process a).

EXAMPLE 109 3-[(3,4-Dihydro-2H-pyrano[3,2-c]pyridinium)-methyl]-7-[2-syn-methoxyimino-2-(2-aminothiazol-4-yl)-acetamido]ceph-3-em-4-carboxylate

A mixture of 6.83 g (15 mmoles) of 7-[2-aminothiazol-4-yl)-2-syn-methoxyimino-acetamido]-cephalosporanic acid, 1.5 g (15 mmoles) of potassium bicarbonate, 24 g (0.25 mole) of potassium thiocyanate, 25 ml of water and 3.4 g (25 mmoles) of 3,4-dihydro-2H-pyrano[3,2-c]pyridine (H. Sliwa and G. Cordonnier, J. Het. Chemistry 12, 809 (1975)), the pH of which had been adjusted by the addition of 2.4 g of 85% strength phosphoric acid to a value of 6.8, was stirred for 2 hours at 68°-70° C. After the batch had cooled down, 200 ml of acetone were added, and the mixture was chromatographed over 400 g of silica gel (Merck 0.063-0.2 mm). The salts were eluted with acetone/water (8:1), and the product was eluted with acetone/water (2:1). The product fractions were lyophilized, and the lyophilizate was rechromatographed over a "Lobar C" column (Merck AG) with acetone/water (2:1). Freeze-drying the product fractions produced 0.9 g of the title compound in the form of a colorless solid.

¹ H-NMR (CF₃ CO₂ D): δ=2.00-2.45 (m, 2H, pyran-H); 2.75-3.30 (m, 2H, pyran-H), 3.52 and 3.75 (AB, J=19 Hz, 2H, SCH₂); 4.25 (s, 3H, OCH₃); 4.4-4.85 (m, 2H, pyran-H); 5.15-6.2 (m, 4H, CH₂ Py and 2-lactam-H); 7.35-7.45 (m, 1Py-H and 1-thiazole-H); 8.3-8.65 ppm (m, 2H, Py).

The compounds which are listed below, correspond to the general formula I in which R¹ denotes hydrogen and R² denotes methyl and, in the pyridinium radical (A in the formula I), carry the substituents indicated in the second column of Table 5, were obtained in a manner analogous to Example 109. The numeral attached to the substituents indicates in each case the exact position of the substituent(s) in the pyridinium radical.

                                      TABLE 5                                      __________________________________________________________________________                        Yield %                                                     Example                                                                             Substituent   of theory                                                                           .sup.1 H-NMR: δ (ppm)                            __________________________________________________________________________     110  3-iso-C.sub.3 H.sub.7                                                                        22                                                                                   ##STR94##                                             111  2-CH.sub.3 -5-CH.sub.3                                                                       23   (CF.sub.3 CO.sub.2 D): 2.59(s, 3H, PyCH.sub.3);                                2.93(s, 3H, PyCH.sub.3);                                                       3.46 and 3.66(AB, J=19Hz, 2H, SCH.sub.2); 4.25(s,                              3H,                                                                            OCH.sub.3); 5.36-6.13(m, 4H, CH.sub.2 Py and 2                                 lactam-H); 7.40                                                                (s, 1H, thiazole); 7.77-8.65(m, 3H, Py)                112  2-CH.sub.3 -4-CH.sub.3                                                                       17   (CF.sub.3 CO.sub.2 D): 2.70(s, 3H, CH.sub.3);                                  2.91(s, 3H, CH.sub.3); 3.47                                                    and 3.67(AB, J=19Hz, 2H, SCH.sub.2); 4.24(s, 3H,                               OCH.sub.3 );                                                                   5.34-6.11(m, 4H, CH.sub.2 Py and 2 lactam-H);                                  7.37(s, 1H,                                                                    thiazole); 7.65-8.56(m, 3H, Py)                        113                                                                                  ##STR95##    28                                                                                   ##STR96##                                             114  3-CH.sub.3 -4-C.sub.2 H.sub.5                                                                18                                                                                   ##STR97##                                             115  4-CH.sub.2 C.sub. 6 H.sub.5                                                                   8                                                                                   ##STR98##                                             116  4-CH.sub.2 -p-C.sub.6 H.sub.4 Cl                                                              7                                                                                   ##STR99##                                             117                                                                                  ##STR100##   11   (CF.sub.3 CO.sub.2 D): 3.57 and 3.85(AB, J=19Hz,                               2H, SCH.sub.2); 4.22(s, 3H, OCH.sub.3);                                        5.36-6.39(m, 4H, CH.sub.2 Py and 2 lactam-H);                                  7.39(s, 1H, thiazole); 7.63(s, 5H, C.sub.6                                     H.sub.5 ); 8.03-9.20(m, 4H, Py)                        118  3-CH.sub.2 -CHCH.sub.2                                                                       21                                                                                   ##STR101##                                            119                                                                                  ##STR102##   20   (CF.sub.3 CO.sub.2 D): 1.79(s, 3H, CCH.sub.3);                                 3.21-4.23(m, 7H, SCH.sub.2, CH.sub.2 C and                                     OCH.sub.3); 4.80-6.31(m, 6H, CCH.sub.2, CH.sub.2                               Py and 2 lactam-H); 7.40(s, 1H, thiazole);                                     7.92-8.91(m, 4H, Py)                                   120  3-CHCHCH.sub.3                                                                               23                                                                                   ##STR103##                                            121  4-CH.sub.2CH.sub.2CHCH.sub.2                                                                 23   (CF.sub.3 CO.sub.2 D): 2.40-3.27(m, 4H,                                        CH.sub.2CH.sub.2); 3.48 and 3.78                                               (AB, J=19Hz, 2H, SCH.sub.2); 4.24(s, 3H,                                       OCH.sub.3); 4.90-                                                              6.24(m, 7H, CHCH.sub.2, CH.sub.2 Py and 2                                      lactam-H); 7.41(s,                                                             1H, thiazole); 7.96 and 8.81(AA'BB', J=6Hz, 4H,                                Py)                                                    122  5-OH-2-CH.sub.3                                                                              13   (CF.sub.3 CO.sub.2 D): 2.86(s, 3H, PyCH.sub.3);                                3,51 and 3.72(AB,                                                              J=18Hz, 2H, SCH.sub.2); 4.26(s, 3H, OCH.sub.3);                                5.37-6.13                                                                      (m, 4H, CH.sub.2 Py and 2 lactam-H); 7.41(s, 1H,                               thiazole);                                                                     7.66-8.39(m, 3H, Py)                                   123  3-OH-4-CH.sub.3                                                                              22   (CF.sub.3 CO.sub.2 D): 2.60(s, 3H, CH.sub.3);                                  3.45 and 3.80 (AB, J=                                                          19Hz, 2H, SCH.sub.2); 4.23(s, 3H, OCH.sub.3);                                  5.15-6.25(m,                                                                   4H, CH.sub.2 Py and 2 lactam-H); 7.41(s, 1H,                                   thiazole);                                                                     7.70-8.75(m, 3H, Py)                                   124                                                                                  ##STR104##                                                                                        ##STR105##                                            125                                                                                  ##STR106##   14                                                                                   ##STR107##                                            126                                                                                  ##STR108##   28   (CF.sub.3 CO.sub.2 D): 1.47(s, 6H,                                             C(CH.sub.3).sub.2); 3.23(bs, 2H, PyCH.sub.2);                                  3.54 and 3.81(AB, J=19Hz, 2H, SCH.sub.2); 4.24(s,                              3H,  OCH.sub.3); 5.29-6.33(m, 4H, CH.sub.2 Py and                              2 lactam-H); 7.41 (s, 1H, thiazole); 7.96-9.00(m,                              4H, Py)                                                127  2-CH.sub.2 OH-4-CH.sub.3                                                                     21                                                                                   ##STR109##                                            128  2-CH(CH.sub.2 CH.sub.2 OH).sub.2                                                              8                                                                                   ##STR110##                                            129  4-CH.sub.2 CH(OH)CH.sub.3                                                                    14   (CF.sub.3 CO.sub.2 D): 1.52(d, J=7Hz, 3H,                                      CH.sub.3); 3.10-4.00(m, 4H,                                                    PyCH.sub.2 and SCH.sub.2); 4.00-4.60(m, 4H,                                    OCH.sub.3 singlet and                                                          CH); 5.25-6.35(m, 4H, CH.sub.2 Py and 2                                        lactam-H); 7.41(s,                                                             1H, thiazole); 8.07 and 8.90(AA'BB', J=6Hz, 4H,                                Py)                                                    130  4-CH.sub.2CH.sub.2CH.sub.2OH                                                                 14                                                                                   ##STR111##                                            131                                                                                  ##STR112##   27   (CF.sub.3 CO.sub.2 D): 1.29-2.17(m, 10H,                                       cyclohexyl); 2.67-4.08(m, 3H, cyclohexyl and                                   SCH.sub.2); 4.23(s, 3H, OCH.sub.3); 5.22-6.39 (m,                              4H, CH.sub.2 Py and 2 lactam-H); 7.39(s, 1H,                                   thiazole); 8.03-9.21(m, 4H, Py)                        132                                                                                  ##STR113##   28   (CF.sub.3 CO.sub.2 D): 1.23-2.24(m, 10H, CH.sub.2                              -cyclohexyl); 2.82-4.10 (m, 3H, CH-cyclohexyl,                                 SCH.sub.2); 4.23(s, 3H, OCH.sub.3); 5.18-6.23 (m,                              4H, CH.sub.2 Py and 2 lactam-H); 7.39(s, 1H,                                   thiazole); 7.93 and 8.82(AA'BB', J=6Hz, 4H, Py)        133                                                                                  ##STR114##   19   (CF.sub.3 CO.sub.2 D): 1.38-4.23(m, 14H,                                       cyclopentyl, SCH.sub.2 and OCH.sub.3); 5.23-6.30(m                             , 4H, CH.sub.2 Py and 2 lactam-H); 7.39(s, 1H,                                 thiazole); 7.88-8.83(m, 4H, Py)                        134                                                                                  ##STR115##   26   (CF.sub.3 CO.sub.2 D): 1.71-2.68(m, 8H,                                        cyclohexenyl), 3.53-3.77(AB, J=19Hz, 2H,                                       SCH.sub.2); 4.23(s, 3H, OCH.sub.3), 5.14-6.19(m,                               4H, CH.sub.2 Py and 2 lactam-H); 7.16(bs, 1H,                                  cyclohexenyl) 7.40 (s, 1H, thiazole); 8.03 and                                 8.69(AA'BB', J=7Hz, 4H, Py)                            135                                                                                  ##STR116##   25   (CF.sub.3 CO.sub.2 D): 1.69-2.04(bs, 4H,                                       cyclohexenyl); 2.21-2.60(m, 4H, cyclohexenyl);                                 3.51 and 3.80(AB, J=19Hz, 2H, SCH.sub.2); 4.23(s,                              3H, OCH.sub.3); 5.24-6.28(m, 4H, CH.sub.2 Py and                               2 lactam-H); 6.51-6.73(m, 1H, cyclohexenyl);                                   7.37(s, 1H, thiazole); 7.85-8.93(m, 4H, Py)            136                                                                                  ##STR117##   20   (CF.sub.3 CO.sub.2 D): 1.99-3.03(m, 6H,                                        cyclopentenyl); 3.50 and 3.77(AB, J=19Hz, 2H,                                  SCH.sub.2); 4.24(s, 3H, OCH.sub.3); 5.15- 6.19(m,                              4H, CH.sub.2 Py and 2 lactam-H); 7.22(bs, 1H,                                  cyclo- pentenyl); 7.41(s, 1H, thiazole); 7.99 and                              8.70(AA'BB', J=6Hz, 4H, Py)                            137                                                                                  ##STR118##   18   (CF.sub.3 CO.sub.2 D): 2.03-3.03(m, 6H,                                        cyclopentenyl); 3.53 and 3.81 (AB, J=19Hz, 2H,                                 SCH.sub.2); 4.23(s, 3H, OCH.sub.3); 5.28-6.32 (m,                              4H, CH.sub.2 Py and 2 lactam-H); 6.79(bs, 1H,                                  cyclopentenyl); 7.41(s, 1H, thiazole);                                         7.89-8.97(m, 4H, Py)                                   138                                                                                  ##STR119##   23   (CF.sub.3 CO.sub.2 D): 1.55-2.06(m, 6H,                                        cycloheptenyl); 2.33-2.84 (m, 4H, cycloheptenyl);                              3.51 and 3.80(AB, J=19Hz, 2H, SCH.sub.2); 4.23(s,                              3H, OCH.sub.3), 5.24-6.61(m, 5H, CH.sub.2 Py, 2                                lactam-H and cycloheptenyl-H); 7.39(s, 1H,                                     thiazole); 7.85-8.86(m, 4H, Py)                        139                                                                                  ##STR120##   16   (CF.sub.3 CO.sub.2 D): 1.04-2.69(m, 10H,                                       methylcyclohexenyl); 3.52 and 3.80(AB, J=19Hz,                                 2H, SCH.sub.2); 4.23(s, 3H, OCH.sub.3); 5.24-6.32(                             m, 4H, CH.sub.2 Py and 2 lactam-H); 6.62(m, 1H,                                methylcyclohexenyl); 7.40(s, 1H, thiazole);                                    7.85-8.94 (m, 4H, Py)                                  140                                                                                  ##STR121##   20   (CF.sub.3 CO.sub.2 D): 1.68-2.21(bs, 10H,                                      cyclohexyl); 3.55 and 3.79(AB, J=19Hz, 2H,                                     SCH.sub.2); 4.23(s, 3H, OCH.sub.3); 5.34- 6.27(m,                              4H, CH.sub.2 Py and 2 lactam-H); 7.37(s, 1H,                                   thiazole); 7.37-9.29(m, 4H, Py)                        141                                                                                  ##STR122##   18   (CF.sub.3 CO.sub.2 D): 2.19(bs, 8H, cyclopentyl);                              3.54 and 3.82(AB, J=19Hz, 2H, SCH.sub.2); 4.23(s,                              3H, OCH.sub.3), 5.35-6.30(m, 4H, CH.sub.2 Py and                               2 lactam-H); 7.37(s, 1H, thiazole); 7.97-9.30 (m,                              4H, Py)                                                142                                                                                  ##STR123##   22   (CF.sub.3 CO.sub.2 D): 1.95(bs, 10H, cyclohexyl);                              3.51 and 3.83(AB, J=19Hz, 2H, SCH.sub.2); 4.24(s,                              3H, OCH.sub.3); 5.24-6.26(m, 4H, CH.sub.2 Py and                               2 lactam-H); 7.39(s, 1H, thiazole); 8.27 and 8.93                              AA'BB', J=6Hz, 4H, Py)                                 143                                                                                  ##STR124##   15   (CF.sub.3 CO.sub.2 D): 2.17(bs, 8H, cyclopentyl);                              3.52 and 3.82(AB, J=19Hz, 2H, SCH.sub.2); 4.23(s,                              3H, OCH.sub.3); 5.26-6.28(m, 4H, CH.sub.2 Py and                               2 lactam-H); 7.39(s, 1H, thiazole); 8.25 and 8.91                              AA'BB', J=7Hz, 4H, Py)                                 144                                                                                  ##STR125##   21   (CF.sub.3 CO.sub.2 D): 1.84(bs, 8H, cycloheptyl);                              2.17(bs, 4H, cyclo- heptyl); 3.54 and 3.81(AB,                                 J=19Hz, 2H, SCH.sub.2); 4.23(s, 3H, OCH.sub.3);                                5.35-6.29(m, 4H, CH.sub.2 Py and 2 lactam-H);                                  7.38 (s, 1H, thiazole); 7.97-9.28(m, 4H, Py)           145                                                                                  ##STR126##   16   (CF.sub.3 CO.sub.2 D): 0.98-2.48(m, 12H,                                       methylcyclohexyl); 3.56 and 3.80(AB, J=19Hz, 2H,                               SCH.sub.2); 4.23(s, 3H, OCH.sub.3); 5.36-6.30(m,                               4H, CH.sub.2 Py and 2 lactam-H); 7.39(s, 1H,                                   thiazole); 7.92-9.32(m, 4H, Py)                        146                                                                                  ##STR127##   17   (CF.sub.3 CO.sub.2 D): 1.91(bs, 8H, cyclopentyl);                              3.39(bs, 2H, PyCH.sub.2); 3.58 and 3.82(AB,                                    J=19Hz, 2H, SCH.sub.2); 4.24(s, 3H, OCH.sub.3);                                5.23-6.27(m, 4H, CH.sub.2 Py and 2 lactam-H);                                  7.42(s, 1H, thiazole); 8.08 and 8.87(AA'BB',                                   J=6Hz, 4H, Py)                                         147                                                                                  ##STR128##   22   (CF.sub.3 CO.sub.2 D): 1.71(bs, 10H, cyclohexyl);                              3.27(bs, 2H, PyCH.sub.2); 3.59 and 3.81(AB,                                    J=19Hz, 2H, SCH.sub.2); 4.23(s, 3H, OCH.sub.3);                                5.19-6.25(m, 4H, CH.sub.2 Py and 2 lactam-H);                                  7.42(s, 1H, thiazole); 8.03 and 8.86(AA'BB',                                   J=6Hz, 4H, Py)                                         148                                                                                  ##STR129##   21   (CF.sub.3 CO.sub.2 D): 1.83-2.30(m, 4H, pyranyl);                              3.03-4.66)(m, 10H, pyranyl, SCH.sub.2 and                                      OCH.sub.3); 5.21-6.26(m, 4H, CH.sub.2 Py and 2                                 lactam-H); 7.39(s, 1H, thiazole); 8.01 and                                     8.93(AA'BB', J=6Hz, 4H, Py)                            149  4-OCH.sub.3 -3-CH.sub.3                                                                      18   (CF.sub.3 CO.sub.2 D): 2.40(s, 3H, CH.sub.3);                                  3.45 and 3.77(AB, J=19Hz,                                                      2H, SCH.sub.2); 4.24(bs, 6H, 2×OCH.sub.3);                               5.03-6.20(m, 4H,                                                               CH.sub.2 Py and 2 lactam-H); 7.41(s, 1H,                                       thiazole); 7.38(d, J=                                                          7Hz, 1H, Py); 8.35-8.85(m, 2H, Py)                     150  3-OCH.sub.3 -4-CH.sub.3                                                                      23   (CF.sub.3 CO.sub.2 D): 2.60(s, 3H, CH.sub.3);                                  3.45 and 3.82(AB, J=19Hz,                                                      2H, SCH.sub.2); 4.13(s, 3H, OCH.sub.3); 4.23(s,                                3H, OCH.sub.3); 5.15-                                                          6.30(m, 4H, CH.sub.2 Py and 2 lactam-H); 7.41(s,                               2H, thiazole);                                                                 7.72-8.60(m, 3H, Py)                                   151  3-OCH.sub.3   21   (CF.sub.3 CO.sub.2 D): 3.50 and 3.83(AB, J=19Hz,                               2H, SCH.sub.2); 4.12                                                           (s, 3H, OCH.sub.3); 4.24(s, 3H, OCH.sub.3);                                    5.17-6.40(m, 4H,                                                               (CH.sub.2 Py and 2 lactam-H); 7.42(s, 1H,                                      thiazole); 7.95-8.80                                                           (m, 4H, Py)                                            152  4-OC.sub.2 H.sub.5                                                                           18                                                                                   ##STR130##                                            153  3-OC.sub.2 H.sub. 5                                                                          24                                                                                   ##STR131##                                            154  3-OCH(CH.sub.3).sub.2                                                                        17   (CF.sub.3 CO.sub.2 D): 1.45 and 1.55(d, J=6Hz,                                 6H, 2CH.sub.3); 3.45 and                                                       3.85(AB, J=19Hz, 2H, SCH.sub.2); 4.24(s, 3H,                                   OCH.sub.3); 4.85                                                               (m, 1H, CH); 5.15-6.35(m, 4H, CH.sub.2 Py and 2                                lactam-H); 7.41                                                                (s, 1H, thiazole); 7.85-8.70(m, 4H, Py)                155  3-OCH.sub.2 CH.sub.2 CH.sub.3                                                                19   (CF.sub.3 CO.sub.2 D): 1.11(t, J=7Hz, 3H,                                      CH.sub.3) 1.62-2.35(m,                                                         2H, CH.sub.2); 3.50 and 3.82(AB, J=19Hz, 2H,                                   SCH.sub.2); 4.00-                                                              4.45(m, 5H, CH.sub.2 and OCH.sub.3); 5.15-6.35(m,                              4H, CH.sub.2 Py and                                                            2 lactam-H); 7.41(s, 1H, thiazole); 7.90-8.75(m,                               4H, Py)                                                156  2-CH.sub.2CH.sub.2OCH.sub.3                                                                  18   (CF.sub.3 CO.sub.2 D): 3.24-4.50(m, 10H,                                       CH.sub.2CH.sub.2, OCH.sub.3 and OCH.sub.3);                                    5.05-6.15(m, 4H, CH.sub.2 Py and 2 lactam-H);                                  7.40(s, 1H,                                                                    thiazole); 7.80-8.83(m, 4H, Py)                        157  4-CH.sub.2CH.sub.2 OC.sub.2 H.sub.5                                                          12   (CF.sub.3 CO.sub.2 D): 1.33(t, J=7Hz, 3H,                                      CH.sub.3); 3.27-4.40(m, 11H,                                                   3CH.sub.2, SCH.sub.2, OCH.sub.3); 5.15-6.30(m,                                 4H, CH.sub.2 Py, 2 lactam-H);                                                  7.42(s, 1H, thiazole); 8.07 and 8.90(AA'BB',                                   J=6Hz,                                                                         4H, Py)                                                158  2-CH.sub.2CH.sub.2OC.sub.2 H.sub.5                                                           20                                                                                   ##STR132##                                            159  4-COCH.sub.3  17   (CF.sub.3 CO.sub.2 D): 2.90(s, 3H, CH.sub.3);                                  3.55 and 3.85(AB, J=19Hz,                                                      2H, SCH.sub.2); 4.24(s, 3H, OCH.sub.3);                                        5.25-6.50(m, 4H, CH.sub.2 Py                                                   2 lactam-H); 7.41(s, 1H, thiazole); 8.57 and                                   9.30(AA'BB',                                                                   J=6Hz, 4H, Py)                                         160  4-CH.sub.2 COCH.sub.3                                                                        12   (CF.sub.3 CO.sub.2 D): 2.53(s, 3H, CH.sub.3);                                  3.50 and 3.85(AB, J=19Hz,                                                      2H, SCH.sub.2); 4.00-4.45(m, 5H, CH.sub.2 and                                  OCH.sub.3); 5.20-6.35(m,                                                       4H, CH.sub.2 Py and 2 lactam-H); 7.41(s, 1H,                                   thiazole); 8.02 and                                                            8.95(AA'BB', J=6Hz, 4H, Py)                            161                                                                                  ##STR133##   19   (CF.sub.3 CO.sub.2 D): 3.53 and 3.81(AB, J=19Hz,                               2H, SCH.sub.2); 4.23(s, 3H, OCH.sub.3); 4.26(s,                                4H, OCH.sub.2) 5.30-6.33(m, 5H, CH.sub.2 Py, 2                                 lactam-H and CHO); 7.39(s, 1H, thiazole); 8.26                                 and 9.04 (AA'BB', J=7Hz, 4H, Py)                       162                                                                                  ##STR134##   21   (CF.sub.3 CO.sub.2 D): 3.59 and 3.84(AB, J=19Hz,                               2H, SCH.sub.2); 4.24(s, 3H, OCH.sub.3); 4.30(s,                                4H, OCH.sub.2); 5.35-6.37(m, 4H, CH.sub.2 Py and                               2 lactam-H); 7.41(s, 1H, thiazole); 8.07-9.21(m,                               4H, Py)                                                163                                                                                  ##STR135##   18   (CF.sub.3 CO.sub.2 D): 1.85(s, 3H, CH.sub.3);                                  3.55 and 3.85(AB, J=19Hz, 2H, SCH.sub.2);                                      3.90-4.55(m, 4H, dioxolane-H); 4.25(s, 3H,                                     OCH.sub.3); 5.30-6.35(m, 4H, CH.sub.2 Py and 2                                 lactam-H); 7.43(s, 1H, thiazole); 8.00-8.35(m,                                 1H, Py); 8.68-9.27(m, 3H, Py)                          164                                                                                  ##STR136##   19   (CF.sub.3 CO.sub.2 D): 1.83(s, 3H, CH.sub.3);                                  3.50 and 3.90(AB, J=19Hz, 2H, SCH.sub.2);                                      3.90-4.55(m, 4H, dioxolane-H); 4.25(s, 3H,                                     OCH.sub.3); 5.20-6.40(m, 4H, CH.sub.2 Py and 2                                 lactam-H); 7.43(s, 1H, thiazole); 8.28 and                                     9.03(AA'BB', J=6Hz, 4H, Py)                            165  4-CH.sub.2CH.sub.2CH.sub.2Cl                                                                 28                                                                                   ##STR137##                                            166  3-CH.sub.2CH.sub.2CH.sub.2Cl                                                                 16   (CF.sub.3 CO.sub.2 D): 2.13-3.77(m, 8H,                                        PyCH.sub.2H.sub.2CH.sub.2 and SCH.sub.2); 4.23                                 (s, 3H, OCH.sub.3); 5.26-6.33(m, 4H, CH.sub.2 Py                               and 2 lactam-H); 7.42                                                          (s, 1H, thiazole); 7.94-8.96(m, 4H, Py)                167                                                                                  ##STR138##   29                                                                                   ##STR139##                                            168                                                                                  ##STR140##   20   (CF.sub.3 CO.sub.2 D): 3.53 and 3.82(AB, J=19Hz,                               2H, SCH.sub.2); 4.24 (s, 3H, OCH.sub.3);                                       5.23-6.26(m, 6H, CH.sub.2 Py, 2 lactam-H and                                   OCH.sub.2); 7.37(s, 5H, C.sub.6 H.sub.5); 8.25                                 and 8.88(AA'BB', J= 7Hz, 4H, Py); 8.28(s, 1H,                                  CH)                                                    169  3-CF.sub.3     9   (CF.sub.3 CO.sub.2 D): 3.55 and 3.90(AB, J=19Hz,                               2H, SCH.sub.2); 4.23(s,                                                        3H, OCH.sub.3); 5.15-6.45(m, 4H, CH.sub.2 Py and                               2 lactam-H); 7.41                                                              (s, 1H, thiazole); 8.15-9.52(m, 4H, Py)                170  3-Br-4-CH.sub.3                                                                              17   (CF.sub.3 CO.sub.2 D): 2.80(s, 3H, CH.sub.3);                                  3.50 and 3.85(AB, J=19Hz,                                                      2H, SCH.sub.2); 4.23(s, 3H, OCH.sub.3);                                        5.10-6.40(m, 4H, CH.sub.2 Py and                                               2 lactam-H); 7.41(s, 1H, thiazole); 7.89(d,                                    J=6Hz, 1H,                                                                     Py); 8.70-9.20(m, 2H, Py)                              171                                                                                  ##STR141##   16   (CF.sub.3 CO.sub.2 D); 3.60 and 3.95(AB, J=19Hz,                               2H, SCH.sub.2) 4.23(s, 3H, OCH.sub.3);                                         5.25-6.55(m, 4H, CH.sub.2 Py and 2 lactam-H);                                  7.40(s, 1H, thiazole); 8.2-9.85(m, 8H, Py)             172  3-CH.sub.2CN  14   (CF.sub.3 CO.sub.2 D): 3.57 and 3.84(AB, J=19Hz,                               2H, SCH.sub.2); 4.23(s,                                                        3H, OCH.sub.3); 4.33(s, 2H, CH.sub.2 CN);                                      5.36-6.41(m, 4H, CH.sub.2 Py and                                               2 lactam-H); 7.40(s, 1H, thiazole); 8.08-9.21(m,                               4H, Py)                                                173                                                                                  ##STR142##   15                                                                                   ##STR143##                                            174  4-CHCHCO.sub.2 CH.sub.3                                                                      21   (CF.sub.3 CO.sub.2 D): 3.55 and 3.83(AB, J=19Hz,                               2H, SCH.sub.2); 4.04                                                           (s, 3H, CO.sub.2 CH.sub.3); 4.24(s, 3H,                                        OCH.sub.3); 5.28-6.36(m, 4H,                                                   CH.sub.2 Py and 2 lactam-H); 7.15 and 7.84(AB,                                 J=16Hz, 2H,                                                                    CHCH); 7.41(s, 1H, thiazole); 8.25 and                                         9.01(AA'BB',                                                                   J=6Hz, 4H, Py)                                         175  3-CHCHCO.sub.2 CH.sub.3                                                                      16   (CF.sub.3 CO.sub.2 D): 3.57 and 3.84(AB, J=19Hz,                               2H, SCH.sub.2); 4.03                                                           (s, 3H, CO.sub.2 CH.sub.3); 4.23(s, 3H,                                        OCH.sub.3); 5.36-6.39(m, 4H,                                                   CH.sub.2 Py and 2 lactam-H); 6.98 and 7.86(AB,                                 J=16Hz, 2H,                                                                    CHCH); 7.40(s, 1H, thiazole); 8.07-9.21(m, 4H,         __________________________________________________________________________                             Py)                                               

The compounds which are listed below, correspond to the general formula I in which R¹ denotes hydrogen and R² denotes methyl and carry the substituent indicated in the second column of Table 6 as the radical A, were obtained in a manner analogous to Example 109.

                                      TABLE 6                                      __________________________________________________________________________                       Yield                                                        Example                                                                             A            % of theory                                                                           .sup.1 H-NMR δ (ppm)                            __________________________________________________________________________     176                                                                                  ##STR144##  21     (CF.sub.3 CO.sub.2 D): 2.1-3.9(m, 6H, 4                                        cyclopentene-H, SCH.sub.2); 4.23 (s, 3H,                                       OCH.sub.3); 5.1-6.4(m, 5H, CH.sub.2 Py,                                        cyclopentene-H, 2 lactam-H); 7.42(s, 1H,                                       thiazole); 7.8-8.9(m, 3H, Py)                         177                                                                                  ##STR145##  17     (CF.sub.3 CO.sub.2 D): 2.3-3.9(m, 8H, 6                                        cyclopentene-H), SCH.sub.2); 4.23 (s, 3H,                                      OCH.sub.3); 5.05-6.3(m, 4H, CH.sub.2 Py, 2                                     lactam-H); 7.40 (s, 1H, thiazole); 7.7-8.8(m,                                  3H, Py)                                               178                                                                                  ##STR146##  15     (CF.sub.3 CO.sub.2 D): 1.8-2.3(m, 4H,                                          cyclohexene-H); 2.7-3.7(m, 6H, SCH.sub.2,                                      cyclohexene-H); 4.23(s, 3H, OCH.sub.3);                                        5.05-6.3(m, 4H, CH.sub.2 Py, 2 lactam-H);                                      7.41(s, 1H, thiazole); 7.6-8.7(m, 3H, Py)             179                                                                                  ##STR147##  18     (CF.sub.3 CO.sub.2 D): 1.8-2.35(m, 4                                           cyclohexene-H); 2.55(s, 3H, CH.sub.3); 2.9-3.7(m,                               6H, SCH.sub.2 and 4 cyclohexene-H); 4.24(s, 3H,                               OCH.sub.3); 5.3-6.25(m, 4H, CH.sub.2 Py, 2                                     lactam-H); 7.41(s, 1H, thiazole); 8.12 and                                     8.42(each 1H, Bs, Py)                                 180                                                                                  ##STR148##  4      (CF.sub.3 CO.sub.2 D): 3.51 and 3.74(AB, J=19Hz,                               2H, SCH.sub.2); 4.24(s, 3H, OCH.sub.3); 5.35(s,                                2H, CH.sub.2); 5.1-6.3(m, 4H, CH.sub.2 Py and 2                                lactam-H); 7.41(s, 1H, thiazole); 7.65-9.05(m,                                 3H, Py)                                               181                                                                                  ##STR149##  3      (CF.sub.3 CO.sub.2 D): 3.52 and 3.75(AB, J=19Hz,                               2H, SCH.sub.2); 4.23(s, 3H, OCH.sub.3);                                        5.0-6.3(m, 7H, CH.sub.2 Py, 2 lactam-H, 3                                      furan-H); 7.41(s, 1H, thiazole); 7.3-8.9(m, 3H,                                Py)                                                   182                                                                                  ##STR150##  5      (CF.sub.3 CO.sub.2 D): 3.3-3.8(m, 4H, SCH.sub.2                                and 2 furan-H); 4.23(s, 3H, OCH.sub.3);                                        4.9-6.4(m, 6H, CH.sub.2 Py, 2 lactam-H, 2                                      furan-H, OCH.sub.2); 7.42(s, 1H, thiazole);                                    7.1-8.4(m, 3H, Py)                                    183                                                                                  ##STR151##  21     (CF.sub.3 CO.sub.2 D): 1.6-2.35(m, 6                                           cycloheptene-H); 3.0-3.95(m, 6H, 4                                             cycloheptene-H and SCH.sub.2) 4.25(s, 3H,                                      OCH.sub.3); 5.25-6.35(m, 4H, CH.sub.2 Py and 2                                 lactam-H); 7.42(s, 1H, thiazole); 7.6-8.73 (m,                                 3H, Py)                                               __________________________________________________________________________

The compounds which are listed below, correspond to the general formula I in which R¹ denotes chlorine and R² denotes methyl and, in the pyridinium radical (A in the formula I), carry the substituents indicated in the second column of Table 7, were obtained in a manner analogous to Example 109. In Example 191, the radical listed in column 2 denotes the radical A in the formula I.

                                      TABLE 7                                      __________________________________________________________________________                   Yield                                                            Example                                                                             Substitutent                                                                            % of theory                                                                           .sup.1 H-NMR: δ (ppm)                               __________________________________________________________________________     184  H        15     (CF.sub.3 CO.sub.2 D): 3.50 and 3.83(AB, J=19Hz, 2H,                           SCH.sub.2); 4.22(s, 3H,                                                        OCH.sub.3); 5.40(d, J=5Hz, C-6-H); 5.1-6.4(AB, 2H,                             CH.sub.2 Py);                                                                  6.08(d, J=5Hz, C-7-H); 7.9-9.2(m, 5H, Py)                 185  3-CH.sub.3                                                                              13     (CF.sub.3 CO.sub.2 D): 2.65(s, 3H, CH.sub.3); 3.68                             and 4.10(AB, J=19Hz, 2H,                                                       SCH.sub.2); 4.20(s, 3H, OCH.sub.3); 5.15-6.30(m, 4H,                           CH.sub.2 Py and 2 lactam-                                                      H); 7.8-9.0(m, 4H, Py)                                    186  3,4-Di-CH.sub.3                                                                         15     (CF.sub.3 CO.sub.2 D): 2.55(s, 3H, CH.sub.3);                                  2.65(s, 3H, CH.sub.3); 3.43 and 3.75                                           (AB, J=19Hz, 2H, SCH.sub.2); 4.20(s, 3H, OCH.sub.3);                           5.1-6.3(m, 4H,                                                                 CH.sub.2 Py and 2 lactam-H); 7.6-8.8(m, 3H, Py)           187  2-CH.sub.2 OH                                                                           11     (CF.sub.3 CO.sub.2 D): 3.54 and 3.82(AB, J=19Hz, 2H,                           SCH.sub.2); 4.23                                                               (s, 3H, OCH.sub. 3); 5.38(s, CH.sub.2 OH);                                     5.2-6.3(m, 4H, CH.sub.2 Py and                                                 2 lactam-H); 7.9-9.0(m, 3H, Py)                           188  4-CH.sub.2 OH                                                                           21     (CF.sub.3 CO.sub.2 D): 3.50 and 3.82(AB, J=19Hz, 2H,                           SCH.sub.2); 4.22                                                               (s, 3H, OCH.sub.3); 5.25(s, CH.sub.2 OH); 5.0-6.2(m,                           4H, CH.sub.2 Py and                                                            2 lactam-H); 8.0-9.1(m, 3H, Py)                           189  4-CH.sub.2 OCH.sub.3                                                                    24     (CF.sub.3 CO.sub.2 D): 3.2-4.1(AB, J=19Hz, 2H,                                 SCH.sub.2); 3.73(s, 3H,                                                         ##STR152##                                                                    (m, 4H, CH.sub.2 Py and 2 lactam-H); 8.0-9.1(AA'BB'                            J=6hZ, 4H,                                                                     Py)                                                       190  4-CONH.sub.2                                                                            17     (CF.sub.3 CO.sub.2 D): 3.52 and 3.82(AB, J=19Hz,                               SCH.sub.2); 4.21(s, 3H,                                                        OCH.sub.3); 5.40(d, 1H, J=5Hz, C-6-H); 5.3-6.5(AB,                             2H, CH.sub.2 Py);                                                              6.08(d, 1H, J=5Hz, C-7-H); 8.57-9.23(AA'BB', J=6Hz,                            4H,                                                                            Py)                                                       191                                                                                  ##STR153##                                                                             20     (CF.sub.3 CO.sub.2 D): 2.2-2.8(m, 2H,                                          cyclopentene-H); 3.1-4.2(m, 6H, 4 cyclopentene-H,                              SCH.sub.2); 4.21(s, 3H, OCH.sub.3); 5.2-6.2(m, 4H,                             CH.sub.2 Py, 2 lactam-H); 7.6-8.6(m, 3H,                  __________________________________________________________________________                          Py)                                                        *Radical A in the formula I                                              

EXAMPLES 192-271

The compounds of Tables 5, 6 and 7 were prepared from the corresponding 7-amino-ceph-3-em-4-carboxylic acid derivatives of the general formula III and 2-(2-aminothiazol-4-yl)-2-syn-oxyiminoacetic acids of the general formula IV in a manner analogous to Example 108 (process b). The compounds are in all respects identical to those of Tables 5, 6 and 7.

EXAMPLE 272 3-[(2,3-Cyclopenteno-1-pyridinium)-methyl]-7-[2-syn-hydroxyimino-2-(2-aminothiazol-4-yl)-acetamido]-ceph-3-em-4-carboxylate

4.3 g (10 mmoles) of 2-(2-tritylamino-1,3-thiazol-4-yl)-2-syn-hydroxyiminoacetic acid, 1.68 g (11 mmoles) of 1-hydroxy-1H-benzotriazole hydrate and 2.48 g (12 mmoles) of dicyclohexylcarbodiimide in 70 ml of N,N-dimethylformamide were used to prepare a solution of the activated ester in a manner analogous to Example 108 b. After 3 hours, this mixture was stirred into a cooled solution at -40° of 4.45 g (11 mmoles) of 7-amino-3-[(2,3-cyclopenteno-1-pyridinium)-methyl]-ceph-3-em-4-carboxylate dihydrochloride, 50 ml of N,N-dimethylformamide and 4 ml (32 mmoles) of N,N-dimethylaniline, and the mixture was left overnight at room temperature. Dicyclohexylurea was filtered off, and the yellow-brown filtrate was added dropwise to 1 l of diethyl ether. Supernatant liquid is decanted off, and the precipitate is stirred together with acetone, filtered off with suction, washed with acetone and dried. The crude product (3.5 g) was dissolved in 30 ml of trifluoroacetic acid and the solution was stirred for 25 minutes at room temperature. The volatile constituents were removed in vacuo, and the residue was digested in ether/n-pentane (2:1), filtered off with suction and washed with the same mixture. The precipitate was then dissolved in 5 ml of water with the addition of sodium bicarbonate, and the solution was chromatographed over a "Lobar C" column (Merck) with acetone/water (2:1). Freeze-drying the product fractions produced 1.1 g (22% of theory) of a colorless amorphous solid.

¹ H-NMR (CF₃ CO₂ D): δ=2.2-2.8 (m, 2H, cyclopentene-H); 3.1-4.1 (m, 6H, cyclopentene-H and SCH₂); 5.2-6.3 (m, 4H, CH₂ Py and 2 lactam-H); 7.48 (s, 1H, thiazole); 7.6-8.6 ppm (m, 3H, Py).

EXAMPLE 273 3-[(4-Cyclopropyl-1-pyridinium)-methyl]-7-[2-syn-hydroxyimino-2-(2-aminothiazol-4-yl)-acetamido]-ceph-3-em-4-carboxylate

From 2-(2-tritylamino-1,3-thiazol-4-yl)-2-syn-hydroxyiminoacetic acid and 7-amino-3-[(4-cylopropyl-1-pyridinium)-methyl]-ceph-3-em-4-carboxylate dihydrochloride by the hydroxybenzotriazole method analogously to Example 272. After elimination of the protective trityl group by means of trifluoroacetic acid and chromatography, the title compound was obtained in the form of a colorless amorphous solid in a yield of 25%.

¹ H-NMR (CF₃ CO₂ D): δ=1.03-2.6 (m, 5H, cyclopropyl); 3.40 and 3.82 (AB, J=19 Hz, 2H, SCH₂); 5.0-6.25 (m, 4H, CH₂ Py and 2 lactam-H); 7.50 (s, 1H, thiazole); 7.64 and 8.66 ppm (AA', BB', J=7 Hz, 4H, Py).

The following compounds were prepared in a manner analogous to Example 272 from the 7-amino-ceph-3-em-4-carboxylate dihydrochlorides of the general formula III and the corresponding 2-(2-amino-1,3-thiazol-4-yl)-2-syn-oxyiminoacetic acids of the general formula IV (R⁴ =H).

EXAMPLE 274 3-[(4-Cyclopropyl-1-pyridinium)-methyl]-7-[2-syn-ethoxyimino-2-(2-aminothiazol-4-yl)-acetamido]-ceph-3-em-4-carboxylate

Colorless solid, yield 28% of theory.

¹ H-NMR (CF₃ CO₂ D): δ=1.1-2.6 (m, 8H, cyclopropyl and CH₂ CH₃ and 1.43); 3.43 and 3.76 (AB, J=19 Hz, 2H, SCH₂) 4.53 (q, J=7 Hz, 2H, CH₂ CH₃); 5.1-6.2 (m, 4H, CH₂ Py and 2 lactam-H); 7.42 (s, 1H, thiazole); 7.63 and 8.66 ppm (AA', BB', J=7 Hz, 4H, Py).

EXAMPLE 275 3-[(4-Cyclopropyl-1-pyridinium)-methyl]-7-[2-(2-amino-5-bromothiazol-4-yl)-2-syn-methoxyimino-acetamido]-ceph-3-em-4-carboxylate

Pale yellow solid, yield 18% of theory.

¹ H-NMR (CF₃ CO₂ D): δ=1.05-2.55 (m, 5H, cyclopropyl); 3.39 and 3.82 (AB, J=19 Hz, 2H, SCH₂); 4.22 (s, 3H, OCH₃); 5.05-6.23 (m, 4H, CH₂ Py and 2 lactam-H); 7.58 and 8.66 ppm (AA', BB', J=7 Hz, 4H, Py).

EXAMPLE 276 3-[(4-Cyclopropyl-1-pyridinium)-methyl]-7-[2-syn-ethoxyimino-2-(2-amino-5-chlorothiazol-4-yl)-acetamido]-ceph-3-em-4-carboxylate

Colorless solid, yield 20% of theory.

¹ H-NMR (CF₃ CO₂ D): δ=1.06-2.48 (m, 8H, cyclopropyl and --CH₂ CH₃ at 1.42); 3.42 and 3.82 (AB, J=19 Hz, 2H, SCH₂); 4.51 (q, J=7 Hz, CH₂ --CH₃); 5.03-6.23 (m, 4H, CH₂ Py and 2 lactam-H); 7.63 and 8.66 ppm (AA', BB', J=7 Hz, 4H, Py).

EXAMPLE 277 3-[(2,3-Cyclopenteno-1-pyridinium)-methyl]-7-[2-syn-isopropyloxyimino-2-(2-aminothiazol-4-yl)-acetamido]-ceph-3-em-4-carboxylate

Colorless solid, yield 23% of theory. ¹ H-NMR (CF₃ CO₂ D): δ=1.47 and 1.57 (d, J=6 Hz, 6H, 2 CH₃); 2.1-2.8 (m, 2H, cyclopentene-H); 3.0-4.2 (m, 6H, 4 cyclopentene-H and SCH₂); 4.8 (m, 1H, CH); 5.1-6.4 (m, 4H, CH₂ Py and 2-lactam-H); 7.41 (s, 1H, thiazole); 7.5-8.6 ppm (m, 3H, Py).

EXAMPLE 278 3-[(2,3-Cyclopenteno-1-pyridinium)-methyl]-7-[2-syn-propyloxyimino-2-(2-aminothiazol-4-yl)-acetamido]-ceph-3-em-4-carboxylate

Colorless solid, yield 21% of theory.

¹ H-NMR (CF₃ CO₂ D): δ=1.08 (t, J=6 Hz, 3H, CH₃); 1.6-2.8 (m, 4H, CH₂ and 2 cyclopentene-H); 3.1-4.2 (m, 6H, 4 cyclopentene-H and SCH₂); 4.53 (t, J=6 Hz, OCH₂); 5.1-6.3 (m, 4H, CH₂ Py and 2 lactam-H); 7.42 (s, 1H, thiazole); 7.4-8.5 ppm (m, 3H, Py).

EXAMPLE 279 3-[(2,3-Cyclopenteno-1-pyridinium)]-methyl-7-[2-syn-ethoxyimino-2-(2-amino-5-chlorothiazol-4-yl)-acetamido]-ceph-3-em-4-carboxylate

Colorless solid, yield 16% of theory.

¹ H-NMR: (CF₃ CO₂ D): δ=1.42 (t, J=7 Hz, 3H, CH₂ CH₃); 2.2-2.8 (m, 2 cyclopentene-H); 3.1-3.85 (m, 6H, 4 cyclopentene-H and SCH₂); 4.50 (q, J=7 Hz, 2H, CH₂ CH₃); 5.15-6.25 (m, 4H, CH₂ Py and 2 lactam-H); 7.6-8.7 (m, 3H, Py).

EXAMPLE 280 3-[(4-Cyclopropyl-1-pyridinium)-methyl]-7-[2-(2-amino-5-chlorothiazol-4-yl)-2-syn-methoxyimino-acetamido]-ceph-3-em-4-carboxylate

Colorless solid, yield 45% of theory.

¹ H-NMR: (CF₃ CO₂ D): δ=1.03-2.55 (m,5H, cyclopropyl); 3.37 and 3.81 (AB, J=18 Hz, 2H, SCH₂); 4.22 (s,3H,OCH₃); 5.03-6.25 (m,4H,CH₂ Py and 2 lactam-H); 7.56 and 8.64 ppm (AA', BB', J=7 Hz, 4H,Py).

EXAMPLE 281 3-[(2,3-Cyclopenteno-1-pyridinium)-methyl]-7-[2-syn-ethoxyimino-2-(2-aminothiazol-4-yl)-acetamido]-ceph-3-em-4-carboxylate

Colorless solid, yield 57% of theory.

¹ H-NMR: (CF₃ CO₂ D): δ=1.43 (t,J=7 Hz, 3H, CH₂ CH₃); 2.2-2.8 (m,2 cyclopentene-H); 305-3.94 (m, 6H, 4 cyclopentene-H and SCH₂); 4.51 (q, J=7 Hz, 2H, CH₂, CH₃); 5.05-6.26 (m,4H, CH₂ Py and 2 lactam-H); 7.42 (s, 1H, thiazole); 7.5-8.75 (m,3H, Py). 

We claim:
 1. A cephem compound of the formula ##STR154## or a physiologically acceptable acid addition salt thereof, wherein R¹ is hydrogen or chlorine, OR² is in the syn-position and R² is C₁ -C₆ -alkyl, and A is a fused bicyclic ring substituent containing pyridinium to which is fused a ring of a di- to decamethylene or a ring of di- to deca-methylene which is mono-substituted by C₁ -C₆ -alkyl.
 2. A cephem compound as in claim 1 or a physiologically acceptable acid addition salt thereof, wherein R¹ is hydrogen, OR² is in the syn-position and R² is methyl or ethyl, and A is pyridinium fused to a ring of trimethylene or tetramethylene.
 3. A cephem compound as in claim 2 or a physiologically acceptable acid addition salt thereof, wherein A is pyridinium fused to a ring of trimethylene.
 4. A cephem compound as in claim 3 or a physiologically acceptable acid addition salt thereof, wherein R² is methyl.
 5. 7-[2-(2-Aminothiazol-4-yl)-2-syn-methoxyiminoacetamido]-3-[(2,3-cyclopenteno-1-pyridinium)-methyl]-ceph-3-em-4-carboxylate or a physiologically acceptable salt thereof.
 6. 7-[2-(2-Aminothiazol-4-yl)-2-syn-methoxyiminoacetamido]-3-[(3,4-cyclopenteno-1-pyridinium)-methyl]-ceph-3-em-4-carboxylate or a physiologically acceptable salt thereof.
 7. 7-[2-(2-Aminothiazol-4-yl)-2-syn-methoxyiminoacetamido]-3-[(5,6,7,8-tetrahydro-1-quinolinium)-methyl]-ceph-3-em-4-carboxylate or a physiologically acceptable salt thereof.
 8. 7-[2-(Aminothiazol-4-yl)-2-syn-methoxyiminoacetamido]-3-[(3,4-cyclohexeno-1-pyridinium)-methyl]-ceph-3-em-4-carboxylate or a physiologically acceptable salt thereof. 